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Rudy B, Maffie J, Amarillo Y, Clark B, Goldberg E M, Jeong H -Y, Kruglikov I, Kwon E, Nadal M and Zagha E (2009) Voltage Gated Potassium Channels: Structure and Function of Kv1 to Kv9 Subfamilies. In: Squire LR (ed.) Encyclopedia of Neuroscience, volume 10, pp. 397-425. Oxford: Academic Press. Author's personal copy
Voltage Gated Potassium Channels: Structure and Function of Kv1 to Kv9 Subfamilies 397
Voltage Gated Potassium Channels: Structure and Function of
Kv1 to Kv9 Subfamilies
B Rudy, J Maffie, Y Amarillo, B Clark, addition, other proteins such as regulatory enzymes E M Goldberg, H-Y Jeong, I Kruglikov, E Kwon, and elements of the cytoskeleton have been shown to þ M Nadal, and E Zagha, New York University School of interact with many K channel molecular complexes. Medicine, New York, NY, USA Based on sequence similarity, the pore-forming sub- þ ã 2009 Elsevier Ltd. All rights reserved. units of mammalian voltage-gated K channels can be classified into three groups of proteins that correspond to distinct functional classes. The first group includes þ Voltage-gated potassium channels have K -selective the proteins of the Kv1–Kv6, Kv8, and Kv9 subfami- pores that are opened by membrane depolarization. lies (collectively called here the ‘KvF family’ for fast- þ þ This opening allows the movement of K ions across activating Kvs), components of voltage-gated K þ the plasma membrane and the generation of K cur- channels that activate quickly upon membrane depo- rents that tend to repolarize the membrane toward larization. In contrast, proteins of the Kv7 subfamily þ the equilibrium potential for K (EK). Voltage-gated (often called the KCNQ family) and of the Kv10– potassium channels contribute widely to the electrical Kv12 subfamilies (also known as the EAG family) þ properties of neurons. They influence subthreshold are pore-forming subunits of voltage-gated K chan- properties, including the resting potential and mem- nels with comparatively slow kinetics. The subunits of þ brane resistance. They influence the amplitude and the Kv7 family form the M-type K channels underly- frequency of subthreshold oscillations, the responsive- ing the current known as IM, a subthreshold operating ness of the cell to synaptic inputs, and the probability current of considerable importance in the regulation of spike generation. They help shape postsynaptic of neuronal excitability. This article discusses the potentials, and they are the main determinants of the channels formed by the pore-forming subunits of the repolarization of the action potential governing spike KvF and Kv7 families (Kv subfamilies 1–9; Figure 1). shape and frequency. Their voltage-dependent activity A separate article in this encyclopedia discusses the more distantly related EAG (Kv10–Kv12) family. ensures a non-ohmic current–voltage relationship, which thereby enables the channels to contribute to the nonlinear properties of neurons. Voltage-gated Structure of Kv Proteins potassium channels have similar functions in other excitable cells, including all varieties of muscle. In non- Kv subunits consist of six membrane spanning domains excitable cells, they contribute to the resting potential (S1–S6) flanked by intracellular NH2 and COOH ter- þ and to the regulation of Ca2 entry and secretion. minal sequences of variable lengths (Figure 1). The þ Voltage-gated K channels differ dramatically in linker between the S5 and S6 transmembrane helices their kinetic and voltage-dependent properties as partially enters the membrane and is known as the þ well as their cellular and subcellular distributions. P loop or P domain. This domain contains the ‘K
This diversity is a main contributor to the varied elec- channel signature sequence’ (TVGYG), which is highly trical properties of neuronal populations throughout conserved not only among Kv proteins but also among þ the nervous system. Thus, understanding the input– all K channel subunits, including those from pro- output relationship of neuronal elements demands the þ karyotes, and contributes to the formation of the K continued effort to study the properties and localiza- selectivepore(Fi gu re s 1 and 2).AttheN-terminus, tion of these channels and analyze their physiological preceding the S1 helix, there is a sequence known as roles in native membranes. the tetramerization or T1 domain. T1 domains of þ Voltage-gated K channels are tetramers of primary, members of the same subfamily are very similar and or pore-forming, subunits (also known as a subunits). determine subfamily specific association. These tetramers form the infrastructure of the channels The fourth membrane spanning domain (S4) is and in most cases are sufficient to form functional characterized by the repetition of a motif consisting þ channels. However, many voltages-gated K channels of two neutral residues (usually hydrophobic except in their natural environment also include associated or toward the COOH end of S4) and one positively auxiliary proteins (sometimes referred to as b subu- charged residue (usually arginine). The number of nits). These proteins have primary sequences not repetitions of this motif is characteristic of each KvF resembling those of the pore-forming subunits, can subfamily: seven in Kv1 subunits, five in Kv2s (as well significantly modify the properties of the channels, as Kv5, Kv6, Kv8, and Kv9) and Kv4s, and six in and can be essential for the efficient expression of Kv3s. The S4 domain in Kv7 (KCNQ) subunits has functional channels in the plasma membrane. In six positive charges, except in Kv7.1, which has four.
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398 Voltage Gated Potassium Channels: Structure and Function of Kv1 to Kv9 Subfamilies
KV1.1 (KCNA1) KV1.2 (KCNA2) KV1.8 (KCNA8) KV1.3 (KCNA3) KV1.4 (KCNA4) KV1.5 (KCNA5) KV1.6 (KCNA6) KV1.7 (KCNA7) KV3.1 (KCNC1) P KV3.2 (KCNC2) KV3.3 (KCNC3) KV3.4 (KCNC4) KV4.2 (KCND2) S1 S2 S3 S4 S5 S6 KV4.3 (KCND3) KV4.1 (KCND1) KV2.1 (KCNB1) KV2.2 (KCNB2) KV9.1 (KCNS1) KV9.2 (KCNS2) KV9.3 (KCNS3)
KV8.1 (KCNV1) T1 domain KV8.2 (KCNV2) KV6.3 (KCNG3) Inactivation ‘ball’ KV6.1 (KCNG1) N (Kv1.4, Kv3.3, Kv3.4) KV6.2 (KCNG2) KV6.4 (KCNG4) KV5.1 (KCNF1) C KV7.2 (KCNQ2) KV7.3 (KCNQ3) KV7.4 (KCNQ4) KV7.5 (KCNQ5) ab KV7.1 (KCNQ1) + Figure 1 (a) Phylogenetic relations of Kv1–Kv9 K channel subunits. The functional classes discussed in this chapter also form closely related subgroups based on sequence similarities. (b) Schematic representation of a Kv subunit. Kv subunits have six membrane spanning domains (S1–S6) flanked by cytoplasmic amino and carboxyl ends. The pore loop region (P), critical to the formation of the K+ channel selectivity filter is found between the S5 and S6 helices. The T1 domain, involved in the formation of tetrameric structures among members of the same subfamily and in interactions with auxiliary proteins, is in the amino end region preceding the S1 domain. Some Kv proteins contain N-inactivation domains at the N-terminus. The membrane is shown in yellow. (a) From Yu FH and Catterall WA (2004) The VGL-chanome: A protein superfamily specialized for electrical signaling and ionic homeostasis. STKE Science’s 253: re15.
The S4 domain is a critical part of the voltage sensor; in Figure 2. The structure of the pore domain is þ þ the positively charged residues are likely the gating similar in voltage-gated K channels and in K chan- charges, which move in response to changes in mem- nels that are not voltage dependent, such as the potas- brane potential to open and close the channel’s pore. sium channels know as inward rectifiers. These The structure of a mammalian Kv channel, a com- channels consist of subunits that have only two heli- plex consisting of four Kv1.2 subunits and four auxil- ces (inner and outer, equivalent to the S6 and S5 iary Kvb 2 proteins, has been resolved at 2.9 A˚ in the helices, respectively) and a P loop. The pore domains laboratory of Roderick MacKinnon (Figure 2a). In the of the four subunits create an ‘inverted teepee,’ or channel structure, four T1 domains, one from each of cone, with the S6 (or inner helix) facing the inside. the four Kv1.2 subunits, interact to form a tetrameric The P loops of the four subunits are located in the assembly at the intracellular membrane surface. This wider third of the teepee, near the extracellular sur- assembly is located directly under the cytoplasmic side face, forming the selectivity filter, which surrounds of the channel’s pore. As a result, the pore communi- the narrowest part of the pore. The selectivity filter is þ cates with the cytoplasm through side portals or win- determined by the amino acids of the K channel dows formed by the linkers connecting the T1 domains signature sequence, oriented in such a way that they to the first membrane spanning helices. These portals expose their main chain carbonyl oxygen atoms to the þ þ allow K ions to flow freely between the pore and the pore. During dehydration of the K ion, these car- cytoplasm. These portals are also large enough to bonyl oxygen atoms replace the oxygen atoms of the allow the entry of the N-terminal inactivating polypep- water hydrating the ion, allowing its entrance into tide responsible for N-type inactivation. Four Kvb2 the narrow pore delimited by the selectivity filter. subunits interact with the T1 domains. The carbonyl oxygens are too far apart to properly þ In the structure derived by MacKinnon and collea- surround and stabilize the smaller Na ion, thus þ gues, the channel consists of two relatively indepen- explaining K selective permeation. dent domains: a voltage sensor domain consisting In the crystal structure, the voltage sensor domain of the S1–S4 helices of the four Kv subunits and a is connected to the pore domain through helices made pore domain consisting of the S5 and S6 membrane by the S4–S5 linker, which makes several amino acid spanning helices with the P loop in between, as shown contacts with the S6 or inner helix lining the pore
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Voltage Gated Potassium Channels: Structure and Function of Kv1 to Kv9 Subfamilies 399
b-Propeller Pore domain
S6 S5 S4
S3 Voltage sensor S2 DPPX domain S1 a/b-hydroxilase S4-S5 domain C T1-S1
T1
N Kv4
Kv b KChip
ab Figure 2 Comparison of the Kv1.2–Kvb2 channel complex with a modeled Kv4.3–KChlP1-DPPX channel complex. (a) Side view of the Kv –Kvb2 channel complex derived from the crystal structure obtained by MacKinnon and colleagues (Long SB, Campbell EB, and 1.2 Mackinnon R (2005) Crystal structure of a mammalian voltage-dependent Shaker family K+ channel. Science 309: 897–903 and Long SB,
Campbell EB, and Mackinnon R (2005) Voltage sensor of Kv1.2: structural basis of electromechanical coupling. Science 309: 903–908). + Image obtained from Wang H, Yan Y, Liu Q, et al. (2007) Structural basis for modulation of Kv4 K channels by auxiliary KChlP subunits. b Nature Neuroscience 10: 32–39. The four Kv1.2 subunits are labeled in cyan, yellow, red, and green. The four Kv 2 subunits are labeled in wheat color. The upper third shows the transmembrane part of the channel. The inverted tepee, formed by the pore domains (S5-P-S6) of the four Kv1.2 proteins, is in the center, and the voltage sensor domains (S1–S4) are lateral. The middle portion of the figure contains the T1 domains interacting with the Kvb2 proteins at the bottom. (b) Side view of the Kv4.3-KChlP1-DPPX channel complex. This figure was obtained by adding molecules of DPPX (based on the crystal structure of the DPPX extracellular domain: obtained by Strop et al. (2004). Strop P, Bankovich AJ, Hansen KC, Garcia KC, and Brunger AT (2004) Structure of a human A-type potassium channel interacting protein DPPX, a member of the dipeptidyl aminopeptidase family. Journal of Molecular Biology 343: 1055–1065) to the model of the Kv4.3-KChlP1 + channel complex by Wang H, Yan Y, Liu Q, et al., Structural basis for modulation of Kv4 K channels by auxiliary KChlP subunits. Nature Neuroscience 10: 32–39. The four Kv4.3 subunits are labeled in cyan, yellow, red, and green. The four KChlP1 proteins interacting with the channel T1 domains, are labeled in blue. The transmembrane domains of DPPX are shown interacting with the membrane spanning helices of the voltage sensor domains. Only two DPPX molecules are shown to facilitate viewing, but we believe that the channel complex is likely to a b b include four DPPX proteins. Each DPPX subunit includes an / hydrolase domain (close to the membrane and a propeller domain shown on top andto the side. The extracellular domains of two DPPX proteins interact forming a dimer.
(Figure 2 ). The cytoplasmic end of the S6 helix is Subunits of the Kv1, Kv3, and Kv4 subfamilies can flexible around a ‘hinge’ provided by the conserved form heteromeric channels with other members of the sequence Pro-X-Pro. The movement of the voltage same subfamily in heterologous expression systems. sensor in response to changes in membrane potential Heteromeric channels have properties that are inter- displaces the S4–S5 linker affecting its interactions mediary to those of homomeric channels, although with the S6 helix, allowing the cytoplasmic end of some properties of one subunit may dominate in the S6 to move and thus constrict or dilate the inner heteromultimeric channel. It is not clear whether the opening of the pore. two members of the Kv2 subfamily can associate with
each other to form heteromeric channels, but both The Fast-Activating Kv Subfamilies can form heteromeric channels with the silent Kv5, Kv6, Kv8, and Kv9 proteins. All members of the Kv1–Kv4 subfamilies form func- Most Kv proteins are expressed in the nervous tional homomultimeric channel complexes when ex- system, and there is considerable overlap of expres- pressed in heterologous expression systems, whereas sion of multiple Kv subunits of the same subfamily in the members of the Kv5, Kv6, Kv8, and Kv9 subfami- many neurons, suggesting that native channels in lies are ‘silent’ pore-forming subunits that do not form many cells might be heteromultimers (Table 1). Het- functional homomultimeric channels by themselves eromultimerization largely increases the number of and must co-assemble with subunits of the Kv2 sub- channels with distinct functional properties that can family to express functional channels. be generated by Kv subunits (the number of different
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otg ae oasu hnes tutr n ucino v oK9Subfamilies Kv9 to Kv1 of Function and Structure Channels: Potassium Gated Voltage
Table 1 a Kv subunits
Channel subunit Associated proteins Expression pattern Channel function Associated pathology
Kv1 subfamily Kvbs (see Table 2) Tissue: strong in brain and sensory Kv1.1 expresses TEA, DTX, and Mouse: knockout – frequent epileptic
Kv1.1 PDZ domain-containing proteins neurons; weak in atria, aorta, 4-AP sensitive fast-activating seizures, short life span. Point b Gene symbol: KCNA1 such as PSD95 and SAP97 skeletal muscle, retina, smooth low-voltage-activating delayed mutation V408A – model of SNAP25, CASPR2 muscle. rectifier channels in heterologous episodic ataxia type-1 (EA1). CNS: RNA – widely expressed expression systems. Spontaneous 11-bp in rodent CNS. In neurons: Kv1.1 subunits contribute deletion – megencephaly. Protein – predominantly in axons, to the formation of dendrotoxin Human: Kv1 mutations – EA1 with þ axon initial segment (AIS), and (DTX-I)-sensitive K channels myokymia, sometimes associated presynaptic terminals. mediating the DTX-sensitive with epilepsy; autoantibodies to Juxtaparanode of myelinated current ID. ID in neuronal somata several Kv1s found in autoimmune fibers. Staining of neuronal somata and AIS regulates neuronal disorders such as Morvan’s and proximal dendrites in some subthreshold excitability and spike syndrome and limbic encephalitis. neurons. initiation as in neurons in the
MNTB, where it ensures that the
timing and pattern of AP firing is preserved across the relay synapse. In presynaptic terminals, it regulates the excitability of the terminal and prevents aberrant excitation. Kv1.2 KVbs. Tissue: brain, vascular smooth In heterologous expression systems, Human: autoantibodies to several Gene symbol: KCNA2 PDZ domain-containing proteins muscle, sensory neurons. Kv1.2 expresses 4-AP and Kv1s found in autoimmune Small GTP-binding protein RhoA. CNS: very widely expressed. Kv1 DTX-sensitive low-voltage- disorders such as Morvan’s Protein tyrosine kinases heteromers often contain Kv1.2. activating delayed rectifier syndrome and limbic encephalitis. phosphorylate and thereby Protein predominantly in axons channels with slower activation
suppress Kv1.2 channels. RhoA is and terminals. Pattern highly kinetics than other Kv1s.
a necessary component in this overlapping with other Kv1s but not Kv1.2 subunits contribute to forming process and mediates M1 receptor identical. For example, in DTX-sensitive channels in inhibition of Kv1.2 by tyrosine hippocampus, cerebellum, and neuronal somata, axons, and phosphorylation. spinal cord. terminals (see Kv1.1). Likely to CASPR2 Present in axon initial segment; contribute to ID with slower juxtaparanode in myelinated axons kinetics. Also in proximal dendrites and soma Regulation of subthreshold in some neurons. excitability in striatal medium spiny neurons.
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Kv1.3 KVbs Tissue: brain, lymphocytes (type n In heterologous expression systems, Kv1.3 / mice have a 1000- to 10 Gene symbol: KCNA3 PDZ domain-containing proteins channel), macrophages, microglia, Kv1.3 expresses fast-activating 000-fold lower threshold for odor PSD95, SAP97, and hDLg kidney, testis and spermatozoa, 4-AP-sensitive channels with detection and increased ability to KCNE4 (MirP3) – an inhibitory osteoclasts. prominent ‘slow’ P/C-type discriminate between odorants. subunit to Kv1.1 and Kv1.3 CNS: prominent in olfactory bulb, inactivation and prominent Mice weigh significantly less than
b1 integrins cerebellum, parallel fibers, deep cumulative inactivation. control littermates, suggesting
nuclei, Purkinje cell somata; weak Blocked by several toxins with some regulation of energy homeostasis
in hippocampus and stratum specificity. as well as peripheral insulin
lucidum. Regulates neuronal excitability, sensitivity. Protein: mitral and granule cells of possibly in heteromers with other Multiple sclerosis: blockers of Kv1.3
the olfactory bulb. Kv1s. are being considered for MS Subfamilies Kv9 to Kv1 of Function and Structure Channels: Potassium Gated Voltage þ Mediates the type n K channel in treatment. lymphocytes, required for lymphocyte activation. Kv1.3 channels contribute to the neuronal killing ability of microglia.
Kv1.4 KVbs Tissue: brain, heart atria, low levels In heterologous expression systems, Kv1.4 / mice show increased Gene symbol: KCNA4 PDZ domain-containing proteins aorta, skeletal muscle Kv1.4 expresses fast-activating spontaneous seizures.
PSD95, SAP97, and hDLg PNS: altered expression after and -inactivating 4-AP-sensitive
a-actinin-2 axotomy; sole Kv1 in channels. Patients with myasthenia gravis
KChaP small-diameter neuron nociceptors Neurons: contributes inactivation to produce autoantibodies to Kv1.4. s þ receptor CNS: mRNA prominent throughout DTX-sensitive K channels. brain, much weaker in cerebellum Regulates spike repolarization and and brain stem. Strong in spike broadening during repetitive hippocampus, striatum, thalamus, activity in mossy fiber terminals. and CX. Heart: mediates slow component of Widespread Kv1.4 Ito in atria. immunoreactivityin brain, probably in axons. Kv1.5 Kvbs Tissue: heart > skeletal muscle > In heterologous expression systems,
Gene symbol: KCNA5 Src tyrosine kinase PDZ-containing brain > lung > kidney. Pancreatic b Kv1.5 expresses fast-activating
proteins cells, microglia, Schwann cells. 4-AP-sensitive delayed rectifier
Kchap channels. Fyn a -actinin-2 Brain: Purkinje cells, DCN. 4-AP-sensitive component of IKslow in Caveolin SAP97 Hippocampus: somatodendritic. mouse ventricle and IKur þ (ultrarapid-activating K current) in human atrium. Potential use in management of atrial fibrillation via blockade of IKur.
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otg ae oasu hnes tutr n ucino v oK9Subfamilies Kv9 to Kv1 of Function and Structure Channels: Potassium Gated Voltage
Table 1 Continued
Channel subunit Associated proteins Expression pattern Channel function Associated pathology
tm1Lex Kv1.6 Kvbs Tissue: brain, smooth muscle, PNS, In heterologous expression systems, Kcna6 lexicon genetics Gene symbol: KCNA6 CASPR2 oligodendrocytes, astrocytes, AV Kv1.6 expresses fast-activating node. subthreshold-activating DTX- and CNS: widely distributed in cerebral 4-AP-sensitive delayed rectifier cortex and hippocampus in axons. channels. Purkinje cells (somatodendritic, Kv1.6 subunits contribute to forming Homozygous mutation results in not axonal) and in various olfactory DTX-sensitive channels in increased thermal nociceptive and amygdaloid structures. neuronal somata, axons, and threshold (MGI).
terminals (see Kv1.1). Autoantibodies to several Kv1s found
in autoimmune disorders such as Morvan’s syndrome, neuromyotonia, and limbic encephalitis. Kv1.7 mRNA: expressed in pulmonary In heterologous expression systems, Gene symbol: KCNA7 arteries, heart, skeletal muscle, Kv1.7 expresses fast-activating pancreatic islet cells, but not in 4-AP-sensitive channels. Two brain. channel isoforms with different functional characteristics; the long form, Kv1.7L, inactivates faster than the short isoform, Kv1.7S,
predominantly due to an N-type
related mechanism, which is impaired in the short form. Kv1.7L, but not mKv1.7S, is regulated by the cell’s redox state. Kv1.8 KCNA4B: increases current RNA expressed in kidney, renal Voltage- and cyclic nucleotide-gated þ Gene symbol: KCNA10 magnitude and sensitivity to cAMP blood vessels, heart, brain K channel. In heterologous (weakly), and aorta expression systems, Kv1.8 expresses slowly activating high-voltage-activating delayed rectifier channels. KCNA10 may facilitate renal
proximal tubular sodium
absorption by stabilizing cell membrane potential. Its presence in endothelial and vascular smooth muscle cells suggests that it also regulates vascular tone.
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Kv2 subfamily Kv2.1 Kv5–Kv6, Kv8–Kv9 subunits Tissue expression: brain, atria, In heterologous expression systems, Gene symbol: KCNB1 KChaP (binds to N-terminus of ventricle, skeletal muscle, olfactory Kv2.1 expresses slowly activating Kv2.1) epithelium, retina, kidney, SCG high-voltage-activating delayed
Fyn SH2 domain (also Kv2.2); spinal motor neurons; rectifier channels that are blocked b SNAP25 lung, pancreatic cells, pulmonary by high millimolar concentrations artery. of TEA. Brain: widely expressed, but no Kv2 channels mediate IK, the detailed distribution of Kv2.1 or TEA-sensitive, 4-AP-‘insensitive’ þ Kv2.2 mRNA or protein reported. delayed rectifier K current
Protein localized in clusters in recorded in many neurons. Subfamilies Kv9 to Kv1 of Function and Structure Channels: Potassium Gated Voltage somatic and proximal dendritic Potential therapeutic targets for membrane. Little neuropil staining. diabetes due to their prominent expression in pancreatic b cells. Kv2.2 Kv5–Kv6, Kv8–Kv9 subunits Tissue: brain, tongue epithelium; In heterologous expression systems, Gene symbol: KCNB2 mKvb 4 associates with Kv2.2 and SCG, sympathetic neurons; GI/ Kv2.2 expresses slowly activating
enhances expression level mesenteric artery smooth muscle. high-voltage-activating delayed
KChaP Brain: neuropil (axons), maybe in rectifier channels that are blocked some somas. by high millimolar concentrations of TEA. Kv2 channels mediate IK, the TEA-sensitive, 4-AP-insensitive þ delayed rectifier K current recorded in many neurons. Kv5.1 Kv2.1 and Kv2.2 subunits Rat and human brain, heart, skeletal Silent subunit, interacts with Kv2 Gene symbol: KCNF1 muscle, liver, cardiac myocytes. subunits and modifies channel Brain: limited mRNA expression in rat properties: decreases current brain – deep cortical layers, levels, slows down activation,
amygdala, and medial habenular produces negative shifts in
nucleus. inactivation, and slows down deactivation. Kv6.1 Kv2.1 and Kv2.2 subunits Human: brain, placenta, skeletal Silent subunit, interacts with Kv2 Gene symbol: KCNG1 muscle. SA cardiac nodal cells. subunits and modifies channel properties: produces negative shifts in activation and inactivation and slows down deactivation. Kv6.2 Kv2.1 and Kv2.2 subunits Primarily rat and human heart. Silent subunit, interacts with Kv2 Gene symbol: KCNG2 subunits and modifies channel properties: modifies kinetics and voltage dependence and confers
submicromolar sensitivity to
antiarrhythmic drug propafenone.
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otg ae oasu hnes tutr n ucino v oK9Subfamilies Kv9 to Kv1 of Function and Structure Channels: Potassium Gated Voltage
Table 1 Continued
Channel subunit Associated proteins Expression pattern Channel function Associated pathology
Kv6.3 Kv2.1 and Kv2.2 subunits Human, rat: brain, testis, thymus, Silent subunit, interacts with Kv2 Gene symbol: KCNG3 adrenal glad, small intestine, subunits and modifies channel kidney, lung, pancreas, ovary, properties: slows down inactivation colon. and deactivation. Brain: widely expressed in rat. RNA
most prominent in cortex,
hippocampus, striatum, amygdala.
Kv6.4 Kv2.1 and Kv2.2 subunits Human: brain, liver, small intestine, Silent subunit, interacts with Kv2 Gene symbol: KCNG4 colon. subunits and modifies channel properties: produces negative shifts in activation and inactivation, slows down deactivation, and speeds up activation. Kv8.1 Kv2.1 and Kv2.2 subunits Hamster brain: mRNA very Silent subunit, interacts with Kv2 Gene symbol: KCNV1 widespread. subunits and modifies channel properties: produces negative shift in inactivation, slows down
activation and inactivation.
Kv8.2 Kv2.1 and Kv2.2 subunits Human: lung, liver, kidney, pancreas, Silent subunit, interacts with Kv2
Gene symbol: KCNV2 spleen, thymus, prostate, testis, subunits and modifies channel ovary, colon. properties: produces small negative shifts in activation and inactivation and slight acceleration of activation. Kv9.1 Kv2.1 and Kv2.2 subunits Human: brain, prostate, testis by Silent subunit, interacts with Kv2 Gene symbol: KCNS1 PCR. subunits and modifies channel Mouse: mainly in brain. properties: reduces currents, mRNA in mouse brain: Kv9.1 and produces negative shifts of Kv9.2 subunits show very similar activation and inactivation. Slows
expression – olfactory bulb, cortex, down activation of Kv2.1. Slows
hippocampus, habenula, down deactivation of Kv2.1 but
basolateral amygdala, cerebellum speeds up deactivation of Kv2.2. Kv9.2 Kv2.1 and Kv2.2 subunits Mouse: mainly in brain Silent subunit, interacts with Kv2 Gene symbol: KCNS2 Pulmonary artery subunits and modifies channel Distribution in mouse brain, (see properties: reduces currents, Kv9.1). produces negative shifts of inactivation. Slows down deactivation of Kv2.1.
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Kv9.3 Kv2.1 and Kv2.2 subunits Widespread expression in human by Silent subunit, interacts with Kv2 Gene symbol: KCNS3 PCR. subunits and modifies channel properties: produces negative shifts of activation and inactivation, slows down deactivation, and speeds up recovery from
inactivation.
Kv3 subfamily Kv3.1 Broadly expressed in somas, axons, In heterologous expression systems, Kv3.1 / mice exhibit impaired Gene symbol: KCNC1 and terminals in brain and spinal Kv3.1 expresses motor skills, hyperactivity, and
cord structures but in specific cell high-voltage-activating, sleep loss. Kv3.1/Kv3.3 double Subfamilies Kv9 to Kv1 of Function and Structure Channels: Potassium Gated Voltage populations, including many (but fast-activating and -deactivating knockout mice show ataxia, not only) GABAergic neurons and delayed rectifier channels that are tremor, myoclonus, and brain stem sensory neurons. very sensitive to TEA and 4-AP. hypersensitivity to ethanol. Dog atrium Molecular basis of canine Important for spike repolarization and
atrial IKur,d . high-frequency firing of brain stem T lymphocytes. auditory neurons and fast-spiking GABAergic interneurons. Regulate
spike repolarization and duration in
presynaptic terminals.
Spike repolarization in nodes of Ranvier in central myelinated axons. Type l channel in T lymphocytes. Kv3.2 Tissue expression: mRNA mainly in In heterologous expression systems, Kv3.2 / mice show alterations in Gene symbol: KCNC2 brain. Kv3.2 expresses cortical EEG and increased high-voltage-activating, seizure susceptibility consistent fast-activating and -deactivating with an impairment of cortical delayed rectifier channels that are inhibitory mechanisms. very sensitive to TEA and 4-AP.
Prominently in thalamus. GABAergic In heteromeric complexes with Kv3.1
interneurons of the neocortex, important for spike repolarization
hippocampus, and caudate; and high-frequency firing of globus pallidus, SNR, sensory fast-spiking GABAergic nuclei in brain stem. interneurons and in spike Protein in terminal fields of repolarization and duration in thalamocortical axons. Somata GABAergic presynaptic terminals. and axons of cortical interneurons Activity modulated by protein kinase and other mRNA-expressing A in heterologous cells and in neurons. neurons. Pancreatic b cells; Schwann cells and (also Kv3.1b); smooth muscle.
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otg ae oasu hnes tutr n ucino v oK9Subfamilies Kv9 to Kv1 of Function and Structure Channels: Potassium Gated Voltage Table 1 Continued
Channel subunit Associated proteins Expression pattern Channel function Associated pathology
Kv3.3 Expressed predominantly in the In heterologous expression systems, Kv3.3 / mice exhibit cerebellar Gene symbol: KCNC3 CNS. Broadly expressed in somas, Kv3.3 expresses dysfunction, altered Purkinje cell axons, and terminals in brain and high-voltage-activating, discharges, and lack spinal cord structures but in fast-activating and -deactivating harmaline-induced tremor. specific cell types. In many (but not channels that are very sensitive to Kv3.1/Kv3.3 double knockout all) GABAergic neurons TEA and 4-AP and inactivate fast mice display severe ataxia, tremor, throughout forebrain and midbrain, in Xenopus oocytes but slowly myoclonus, and hypersensitivity to and in mossy fiber axons of and variably in mammalian ethanol. dentate granule cells in transfected cells. Human: mutations in Kv3.3 cause þ þ hippocampus. Very strongly Regulation of Na and Ca2 spike spinocerebellar ataxia SCA13.
expressed in cerebellum, repolarization and spontaneous
particularly in Purkinje cell somas, firing frequency of Purkinje cells. axons, and dendrites. Expression May contribute to Kv3.1-containing in brain stem sensory and reticular channels in auditory brain stem neurons and motor neurons. (see Kv3.1). Channels probably containing Kv3.3 and Kv3.4 regulate transmitter release at motor end plates, and channels containing Kv3.1 and Kv3.3 transmitter release from cerebellar parallel fiber terminals. Kv3.4 MiRP2 forms potassium channels in Prominent in skeletal muscle. In heterologous expression systems, Human: an R83H missense mutation
Gene symbol: KCNC4 skeletal muscle with K 3.4. Brain: weakly in hippocampal granule Kv3.4 expresses in MiRP2 that diminished the V cells, Purkinje cells, and pontine high-voltage-activating, effects of MiRP2 on Kv3.4 is nuclei. fast-activating and fast-inactivating associated with periodic paralysis. channels that are very sensitive to TEA and 4-AP. In association with MirP2, forms low-voltage-activating potassium channels that regulate skeletal muscle resting potential. Channels probably containing Kv3.3 and Kv3.4 regulate transmitter release at motor end plates.
Kv4 subfamily
Kv4.1 Not investigated Rat brain: mRNA very weakly In heterologous expression systems, þ Gene symbol: KCND1 expressed in rat. Kv4.1 expresses transient K Expressed in human brain, uterus. currents blocked by millimolar concentrations of 4-AP with slower inactivation kinetics than Kv4.2 and Kv4.3.
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Kv4 channels underlie the fast transient outward current Ito in cardiac myocytes and most of the subthreshold-operating somatodendritic A-type K current
in mammalian neurons (ISA ).
However, Kv4.2 and Kv4.3 appear
to be the main Kv4 subunits in
brain and heart. Kv4.2 KChIPs, DPPX (DPP6), and DPP10 mRNA: brain – expressed in In heterologous expression systems, Mouse: the loss of Kv4.2 protein in
Gene symbol: KCND2 selective brain areas, sometimes Kv4.2 expresses hippocampal CA1 pyramidal Subfamilies Kv9 to Kv1 of Function and Structure Channels: Potassium Gated Voltage overlapping with Kv4.3 (e.g., low-voltage-activating, neurons of Kv4.2 produces a near- þ thalamus), but often in areas not fast-inactivating K currents that complete elimination of ISA from expressing Kv4.3 (predominant recover quickly from inactivation apical dendrites, resulting in an form in the caudate putamen, and are blocked by millimolar increase in the amplitude of pontine nucleus, and several concentrations of 4-AP resembling backpropagating action potentials
nuclei in the medulla); granule cells neuronal ISA . Native-like properties and an increase of concomitant þ in the OB; CA1 pyramidal cells in are enhanced by association with Ca2 influx, facilitating the the hippocampus; reciprocal associated proteins KChIPs and induction of long-term potentiation.
expression with Kv4.3 in the DPPs.
cerebellar granule cell layer. Protein: predominantly dendritic Kv4 channels underlie the fast In dorsal horn neurons, genetic expression in hippocampal transient outward current Ito in elimination of Kv4.2 increases pyramidal cells and cerebellar cardiac myocytes and most of the excitability, resulting in enhanced granule cells. subthreshold-operating sensitivity to tactile and thermal Heart: rodent ventricular muscle. somatodendritic A-type K current stimuli. Furthermore, (ISA ) in mammalian neurons. ISA ERK-dependent forms of pain regulates firing frequency in hypersensitivity are absent in neurons and dendritic excitability. Kv4.2 / mice. Kv4.3 KChIPs, DPPX (DPP6), and DPP10 Kv4.3 mRNA predominant Kv4 in In heterologous expression systems, Gene symbol: KCND3 cortical GABAergic interneurons, Kv4.3 expresses
cerebellar Purkinje cells and low-voltage-activating, þ dopaminergic neurons in fast-inactivating K currents that substantia nigra pars compacta, recover quickly from inactivation restrosplenial cortex, superior and are blocked by millimolar colliculus, raphe, and amygdala; in concentrations of 4-AP resembling cerebellar granule cells, neuronal ISA . Native-like properties predominant in posterior lobules. are enhanced by association with Protein: strong expression in associated proteins KChIPs and dendrites. DPPs. Kv4.3 kinetics is somewhat Heart: Kv4.3 main Kv4 gene in slower than that of Kv4.2. canine and human ventricle.
Continued
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otg ae oasu hnes tutr n ucino v oK9Subfamilies Kv9 to Kv1 of Function and Structure Channels: Potassium Gated Voltage Table 1 Continued
Channel subunit Associated proteins Expression pattern Channel function Associated pathology
Kv4 channels underlie the fast transient outward current Ito in cardiac myocytes and most of the subthreshold-operating þ somatodendritic A-type K current (ISA ) in mammalian neurons. ISA regulates firing frequency in neurons and dendritic excitability. The pacemaker frequency of individual dopaminergic neurons,
and hence the amount of
dopamine release, correlates with
ISA levels, which in turn correlate with the concentration of Kv4.3 mRNA Kv7 (KCNQ) family Kv7.1 (also known as KCNE1(MINK) Heart, kidney, colon, pancreas, lung, Slow sustained current. Does not Human: KCNQ1 loss-of-function KvLQT1) KCNE2(MiRP1) pituitary, cochlea (marginal cells of associate with other Kv7 subunits. mutations cause long QT syndrome Gene symbol: KCNQ1 KCNE3(MiRP2) stria vascularis), placenta. Co-assembles with minK/KCNE1 (including Romano–Ward Exocrine pancreas. to form the cardiac IKs channel syndrome and Jervell and involved in repolarization of Lange-Nielsen syndrome (JLNS)). cardiac action potentials and in JLNS includes deafness;
epithelial cells of the inner ear, gain-of-function mutations in þ where they mediate K secretion KCNQ1 cause atrial fibrillation and
into the endolymph. Associates short QTsyndrome. Associated with with KCNE3 to form leakage Beckwith–Wiedemann syndrome. channels involved in intestinal Knockout mouse: model of JLNS. chloride secretion. Kv7.2 Calmodulin Expressed mainly in neural tissue: Slow delayed rectifier in Human: benign familial neonatal Gene symbol: KCNQ2 Kv7.3, CNS, pituitary, SCG, heterologous cells. Associates convulsions (BFNC) Tubulin, PKA thoracolumbar ganglia. Widely with Kv7.3 to form M-type Mouse: KCNQ2-/- mice die soon KCNE2 expressed in many neuronal channels. Highly TEA sensitive in after birth due to pulmonary populations also expressing Kv7.3. homomultimeric channels. atelectasis. KCNQ2+/- mice have Highest levels of both Kv7.2 and Sensitivity to TEA drops to increased seizure susceptibility. Kv7.3 expression are found in the millimolar concentrations when
cerebral cortex, striatum, associated with other Kv7
hippocampus, thalamus, reticular subunits. Blocked by M-channel nucleus of thalamus, anterior blockers XE991 and linopirdine. olfactory nucleus, and red nucleus. Activated by the M channel opener Protein expression in neuronal Retigabine. somata, Nodes of Ranvier and axon initial segment.
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Kv7.3 Kv7.2, Kv7.4, KCNQ5, calmodulin, See Kv7.2. Slow delayed rectifier in Human: BFNC. Gene symbol: KCNQ3 tubulin, PKA heterologous cells. Associates KCNE2 with Kv7.2, Kv7.4, and Kv7.5 to form M-type channels. Blocked by M-channel blockers XE991 and linopirdine. Activated by the M
channel opener retigabine.
Kv7.4 Kv7.3 Brain stem auditory neurons Slow delayed rectifier in Human: mutations in KCNQ4 cause
Gene symbol: KCNQ4 (cochlear nuclei, nuclei of the heterologous cells. Associates autosomal dominant lateral lemniscus, and inferior with Kv7.3 to form M-type nonsyndromic deafness type 2
colliculus). Cochlea (outer hair channels. Blocked by M-channel (DFNA2). Subfamilies Kv9 to Kv1 of Function and Structure Channels: Potassium Gated Voltage cells (OHC)), inner hair cells (IHC), blockers XE991 and linopirdine. Mouse: degeneration of OHCs and vestibular hair cells). Activated by the M-channel opener progressive hearing loss. DFNA2 Protein in basal membrane of OHC, retigabine. might be caused by a slow in type I hair cells in vestibular In OHCs, currents are large and degeneration of OHCs resulting organs, and in the calyx-like constitute the dominant currents at from chronic depolarization. terminals on these cells. rest and during depolarization. þ Principal exit pathway for K ions entering the cells through the
transduction channels. In IHCs,
the current is relatively small and it influences mainly resting membrane properties. Kv7.5 Kv7.3 CNS, SCG, sympathetic ganglia, Slow delayed rectifier in Gene symbol: KCNQ5 Calmodulin overlapping with Kv7.2 and Kv7.3 heterologous cells. Associates in several brain regions (cortex, with Kv7.3 to form M-type hippocampus, and striatum). Also channels. Blocked by M-channel expressed in skeletal muscle. blockers XE991 and linopirdine. Protein: pyramidal cells and interneurons in neocortex and hippocampus. aFor additional details and references: see IUPHAR Ion Channel Compendium 2005, Pharmacol Rev 57: 473–508 (2005) and the tables in our site: http://www.med.nyu.edu/rudylab, search gene using gene name at http://www.ncbi.nlm.nih.gov/sites/entrez; additional molecular information can also be obtained from the Jackson’s laboratory Mouse Genome Informatics (MGI) site: http://www.informatics.jax.org. b Per convention, human gene names use uppercase and mouse names lowercase (e.g., KCNA1 and Kcna1, respectively).
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410 Voltage Gated Potassium Channels: Structure and Function of Kv1 to Kv9 Subfamilies subunit combinations can be calculated from the equa- of magnitude, from tens of milliseconds to seconds. tion [p þ (n-1)]!/[p!(n-1)], where p is the aggregation The rate of P/C inactivation depends on the amino number (4), and n is the total number of different acid sequence of both the P domain and the S6 subunits that can heteromultimerize), predicting an domain, and it can be affected by extracellular ions enormous diversity of channels, which is even larger if that interact with the channels pore. one considers other factors that can also lead to func- Next, we discuss the physiological contributions tional diversification, such as interactions with diverse and other salient features of each of the four groups auxiliary proteins or posttranslational modifications. of KvF proteins in mammalian species. Given the subfamily specific heteromultimeriza- tion, each Kv subfamily describes an independent functional unit. This emphasizes the need to discuss Kv1 (Shaker) Subfamily each subfamily as a group, as we do in this article. As This is the largest Kv subfamily, with eight genes described previously, the members of the Kv5, Kv6, identified to date (Table 1). However, we focus on Kv8, and Kv9 subfamilies must co-assemble with the first six members of the subfamily (Kv1.1–Kv1.6). subunits of the Kv2 subfamily to form functional Kv1.7, the only Kv1 gene known to produce more channels. Therefore, they are integral parts of Kv2 than one protein isoform, is prominently expressed in channels and are treated together with the members cardiac and skeletal muscle, as well as in pancreatic of the Kv2 subfamily. Members of the Kv1–Kv4 sub- islet cells, but not in the nervous system. Kv1.8 (better families are homologs of the Shaker, Shab, Shaw, and known as KCNA10), the most recently identified Kv1 Shal genes in Drosophila, respectively. Therefore, the gene, is intriguing because it is structurally and func- mammalian counterparts are sometimes referred to tionally related to both voltage-gated and cyclic using the nomenclature in flies (e.g., Kv1 or Shaker nucleotide-gated channels. Although RNAse protec- genes or channels). tion analysis has suggested that KCNA10 transcripts are present in brain, nothing is known about its func- N- and C/P-Type Inactivation of Kv Channels tion in neural cells.
þ Kv1.1–Kv1.6 subunits are components of voltage- Voltage-gated K channels (as well as most other þ gated K channels, which overall tend to activate voltage-gated channels except the HCN pacemarker faster and at lower membrane potentials than Kv channels) activate and open upon membrane depolar- channels of the Kv2 and Kv3 subfamilies. (Several ization. However, most Kv channels do not remain Kv1 channels also tend to activate at more negative open, even if the depolarization remains constant, membrane potentials than Kv4 channels; however, but undergo a process known as inactivation. The the voltage-dependence of Kv4 channels is shifted rates at which the channels inactivate vary by orders toward more negative voltages by interaction with of magnitude depending on the channel type: Fast- their auxiliary proteins DPPX and DPP10.) They inactivating channels mediating transient (or A-type) þ can conduct current at voltages below threshold for K currents inactivate with time constants in the spike generation and therefore contribute to the sub- range of 10–100 ms. There are probably several threshold properties of neurons. They are also highly mechanisms by which Kv channels inactivate, two sensitive to 4-aminopyridine (4-AP), with IC s of which have been well characterized: N- and 50 of <1 mM for all Kv1.1–Kv1.6 homomeric channels. P/C-type inactivation. N-type inactivation is usually Most Kv1 proteins are widely and prominently fast and is produced by the cytoplasmic N-terminal expressed in neurons throughout the nervous system, sequence of some Kv subunits, which acts as a peptide except for Kv1.5, Kv1.7, and Kv1.8 (Table 1). It is that enters and occludes the channel’s pore, blocking likely that most, if not all, neurons in the central ion permeation. The following Kv pore-forming sub- nervous system (CNS) and peripheral nervous system units – Kv1.4, Kv3.3, and Kv3.4 – as well as the Kv1 (PNS) express several Kv1 proteins. This suggests that auxiliary proteins Kvb1 and Kvb3 contain such native Kv1 channels in many cells might be hetero- N-terminal inactivation domains, producing N-type meric complexes of several Kv1 proteins. inactivation of channels containing one or more of these subunits. Neuronal Kv1.1–Kv1.6 channels are complexes of P/C-type inactivation is produced by a time- Kv1 and Kvb subunits dependent conformational change that constricts the external mouth of the pore (a ‘pore collapse’), Pongs and colleagues discovered a group of proteins although the molecular details are not completely now known as Kvb subunits that associate with Kv1 understood. Many Kv channels undergo P/C inacti- pore-forming subunits. Kvb proteins identified to vation, but the rates can differ by two or three orders date are products of three genes, Kvb1–Kvb3, each
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Voltage Gated Potassium Channels: Structure and Function of Kv1 to Kv9 Subfamilies 411 of which produces several isoforms by alternative In addition, by virtue of their N-type inactivation splicing at the N-terminal region (Table 2). They domain, Kvb1 and Kvb3 proteins can accelerate the have a mass of approximately 40 kDa and lack puta- inactivation of Kv1.4-containing channels or induce tive transmembrane domains, potential glycosylation fast inactivation in otherwise non-inactivating or sites, or leader sequences, suggesting that they are slowly inactivating Kv1 channels (except in Kv1.3, cytosolic proteins. This has been confirmed by struc- for which inactivation is not affected by Kvb1 and tural analysis. Kvb proteins bind 1:1 to the T1 Kvb3, and Kv1.6, for which inactivation is not b domain located in the N-terminal region of the chan- affected by Kv 1). Kv1.6 proteins contain an N-type nel pore-forming subunits, creating channel com- inactivation prevention domain that prevents inacti- plexes of eight polypeptides (Figures 1(b) and 2(a)). vation of channels containing one or more Kv1.6 In fact, it is likely that most, if not all, Kv1 channels subunits. On the other hand, Kvb2 proteins, which in neural cells are complexes that resemble the struc- lack N-terminal inactivation domains, accelerate ture shown in Figure 2a, containing four Kv1 pore- inactivation only when Kv1.4 subunits form part of forming subunits and four Kvb associated proteins. the Kv1 channel complex, probably via interactions b All Kv subunits share a conserved core domain, with the intrinsic Kv1.4 inactivation domain. Thus, which has sequence and structural similarity to the Kvb subunits diversify the inactivating properties aldo-keto reductases. In addition, the Kvb1andKvb3 of Kv1 channels. In some cases, the Kvb subunits may subunits contain an extra, isoform-specific, N-terminal also shift the voltage dependence of activation in the sequence that resembles the inactivation domain found hyperpolarizing direction. in Kv1.4, which produces N-type inactivation. The amino acid sequence and structural similarity A key function of the Kvb subunits is to act as with aldo-keto reductases has remained an intriguing chaperones during channel biosynthesis, facilitating feature. One study has provided data suggesting that proper trafficking and expression at the cell surface. Kvb proteins may actually function as redox
Table 2 Kv b accessory subunitsa
Subunit Spliced isoforms Expression patternb Function (with accession
numbers)
Kvb1 Kvb1.1:NM_172159 Widely distributed in brain tissue with Structural component of Kv1 channels. Gene symbol: Kvb1.2:NM_003471 cell-specific distribution. Co-expressed Facilitate trafficking and expression at
KCNAB1 Kvb1.3:NM_172160 with Kv1.1 and Kv1.4 in cortical cell surface. Accelerate inactivation of
interneurons, in the hippocampal Kv1 channels. Cell metabolic state perforant path and mossy fiber pathways, sensor. and in the globus pallidus and substantia nigra. Kv1.1 and Kv1.4 and, to a lesser extent, Kv1.2 and Kv1.6 are detected in channel complexes containing Kvb1. MostofthesealsocontainKvb2. More prominent in young animals (before P21). Kvb2 Kvb2.1:NM_003636 Widely distributed in brain tissue; more Structural component of Kv1 channels. Gene symbol: Kvb2.2:NM_172130 abundant in adult brain than Kvb1. Facilitate trafficking and expression at KCNAB2 Co-expressed with Kv1 subunits in the cell surface. Only accelerate
juxtaparanode in myelinated fibers. The inactivation of Kv1.4 channels. Cell þ bulk of K channel complexes in brain metabolic state sensor. containing Kv1.1, Kv1.2, Kv1.4, and Kv1.6 contain Kvb2. Kvb3 Kvb3.1: (human, rat) More restricted pattern of expression than Structural component of Kv1 channels. Gene symbol: NM_004732 Kvb1 and Kvb2. No high-resolution Facilitate trafficking and expression at KCNAB3 Kvb3.2 (first localization studies. Most prominent in cell surface. Accelerate inactivation of named Kvb4): cerebellum. Also expressed in Kv1 channels. Cell metabolic state (mouse) U65593 neocortex. sensor. aData from Jackson’s laboratory Mouse Genome Informatics website, http://www.informatics.jax.org , and from Coetzee WA, Amarillo Y, Chiu J, et al. (1999) Molecular diversity of Kþ channels. Annals of the New York Academy of Sciences 868: 233–285; and Pongs O, þ Leicher T, Berger M, et al. (1999) Functional and molecular aspects of voltage-gated K channel beta subunits. Annals of the New York Academy of Sciences 868: 344–355. bData derived largely from Rhodes KJ, Strassle BW, Monaghan MM, Bekela-Arcuri Z Matos MF, and Trimmer JS Association and colocalization of the Kvb1 and Kvb2 b-subunits with Kv1 a-subunits in mammalian brain Kþ channel complexes. Journal of Neuroscience 17: 8246–8258.
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412 Voltage Gated Potassium Channels: Structure and Function of Kv1 to Kv9 Subfamilies enzymes. It was observed that Kvb2 can use 4-cyano- capable of producing fast N-type inactivation. Kv1.4 benzaldehyde as a substrate and reduce it to an alco- subunits contribute fast inactivation to heteromulti- hol. The catalytic reaction was found to be very slow, meric channels. The rate of inactivation of a hetero- suggesting that this might not be the primary function meric channel depends on the number of inactivating b of Kv proteins. Instead, it has been suggested that subunits in the channel complex. In addition, as the Kvb s endow Kv1 channels with a sensor module described previously, several Kvb subunits have to detect the metabolic state of the cell. This hypoth- N-terminal inactivation domains which confer fast esis is based on the observation that application of the N-type inactivation to Kv1 channels, including those substrate to the cytoplasmic side of the cell influenced with slow or no inactivation. Therefore, the inactiva- the rate of inactivation of Kv1.4–Kvb2 complexes. tion rate of native channels will depend on subunit All Kv b subunits are predominantly expressed in composition, in terms of all the subtypes of pore- brain tissue. Kvb1 and Kvb2 are widely distributed forming subunits in the channel complex as well as but display cell-specific distributions. Kvb2 proteins the type of Kvb present. Furthermore, inactivation are much more abundant, and a much larger portion mechanisms can be the subject of posttranslational of the total brain pool of Kv1-containing channel modifications, and these modulations can change complexes is associated with Kvb2 rather than with inactivation properties of native channels. þ Kvb1. Complexes containing Kvb1 often also contain K channels containing Kv1.4 proteins, with or b b b Kv 2. Kv 3 shows a more restricted pattern of without Kv subunits, recover from inactivation very expression (Table 2). slowly, resulting in cumulative inactivation during Kv1.8 (KCNA10) interacts specifically with the repetitive activity. It has been suggested that this med- auxiliary subunit KCNA4B, which is unrelated to iates activity-dependent spike broadening in hippocam- b the Kv subunits. When co-expressed with KCNA10, pal mossy fiber boutons (MFBs), the large presynaptic KCNA4B increases KCNA10 current and also terminals of the axons of the granule cells of the dentate increases its sensitivity to activation by cAMP. gyrus. The action potential in these terminals is very b In addition to association with Kv subunits, most brief during low-frequency stimulation but is pro- Kv1 proteins are able to interact with scaffolding, longed up to threefold during high-frequency stimula- membrane-associated putative guanylate kinases (or tion. Prolongation of the presynaptic spike results in an 2þ MAGUKs), which are PDZ domain-containing pro- increase in the number of Ca ions entering the termi- teins such as PSD-95 and SAP97. The association is nal per action potential, and this in turn leads to poten- important for the clustering of the channels in micro- tiation of evoked excitatory postsynaptic currents at domains at the neuronal surface, and it is mediated MFB–CA3 pyramidal cell synapses. by the interaction of the PDZ domains with the Many Kv1 channels inactivate slowly via P/C-type C-terminus of Kv1 proteins, which has the sequence inactivation. This inactivation is prominent in Kv1.3 ETDV or ETEV (except for Kv1.8). Mutation of this channels. Due to the slow rates of recovery from
C-terminal sequence abolishes binding to the inactivation, P/C inactivation of Kv1.3 channels pro- MAGUKs and prevents channel clustering. duces pronounced cumulative inactivation during repetitive stimulation. Functional properties of Kv1 channels Kv1 channels mediate dendrotoxin-sensitive Kv1 channels can be delayed rectifiers or fast-tran- þ K currents sient A-type channels, depending on their subunit composition. Delayed rectifier channels are slowly Three Kv1 subunits – Kv1.1, Kv1.2, and Kv1.6 – inactivating voltage-gated potassium-selective ion express homomultimeric channels which are blocked channels so called because potassium flux occurs in by the mamba snake toxins dendrotoxin I (DTX-I) a voltage- and time-dependent manner with a delay and a-dendrotoxin (a-DTX). In heteromeric chan- after a depolarizing voltage step, which is longer than nels, a single Kv1.1, Kv1.2, or Kv1.6 protein is suffi- the time required to activate fast inward sodium cur- cient to confer DTX sensitivity. Hence, Kv1 channels rents (hence, delayed) and normally flows in one are the mediators of the D-type current or ID. This direction (outward; hence, producing rectification of current, originally described in CA1 pyramidal neu- þ the current–voltage relation). The term A-type K rons, is of great interest due to its effects on the sub- channels or ‘A channels’ is applied to voltage-gated threshold properties of neurons. Given the þ K channels that inactivate fast during depolarization heteromeric association of Kv1 proteins, the wide- < (usually with time constants of 100 ms in mammals). spread expression of Kv1.1, Kv1.2, and Kv1.6 pro- Among the Kv1 subunits prominently expressed in teins in the nervous system (Table 1), and the total brain (Kv1.1–Kv1.6), Kv1.4 subunits are the only number of Kv1 pore-forming subunits and Kvbs, the ones that contain an N-terminal inactivation domain possible combinations of subunits producing channels
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Voltage Gated Potassium Channels: Structure and Function of Kv1 to Kv9 Subfamilies 413 containing one of the Kv1 subunits conferring DTX does not seem to contribute to the repolarization of sensitivity is extremely large, resulting in a large diver- the action potential. sity of ID with variations in a number of properties In myelinated axons, Kv1.1, Kv1.2, and Kv1.6 are including inactivation rates. For example, a channel present in the juxtaparanodal region (Figure 6). b containing Kv1.1, Kv1.4, and Kv 1, a combination Although their role here is not clear, it has been that has been detected in hippocampus, will produce a suggested that they may function to dampen re- fast-inactivating DTX-sensitive current. Inactivation entrant excitation. This juxtaparanodal localization would be much slower if the channel contained Kvb2 is affected by demyelination. Myelin loss results in the þ instead of Kvb1. Similarly, Kv1.2 homomultimers exposure and dispersion of these juxtaparanodal K activate more slowly than other Kv1.1–Kv1.6 chan- channels – effects that in turn contribute to the neu- nels (Table 1); thus, the presence of Kv1.2 subunits rological symptoms associated with demyelination. will leadto ID with slower activation kinetics. Kv2 (Shab) Subfamily Mutations in the gene encoding Kv1.1 cause There are two known members of this subfamily, episodic ataxia type 1 and epilepsy Kv2.1 and Kv2.2. Both are widely expressed in Consistent with their role in regulating neuronal sub- brain tissue and are believed to be present in threshold excitability, mutations in the human many, if not all, principal cells and interneurons KCNA1 gene encoding Kv1.1 proteins produce a throughout the brain. In contrast to the other KvF disease with perturbed excitability – episodic ataxia families, in which heteromultimer formation is prev- type 1 (EA1) with myokymia, an autosomal domi- alent, immunohistochemistry shows that the two nant disease affecting central and peripheral nerve Kv2 subunits produce distinct subcellular staining function, sometimes associated with epilepsy. Simi- patterns even in cells that express both proteins, larly, Kv1.1 knockout mice have severe, often lethal, suggesting that Kv2 subunits may not form heteromul- epilepsy. Although the cellular basis for the height- timeric channels in vivo. Furthermore, immunoprecipi- ened seizure susceptibility of the mice is not under- tation experiments failed to show association of the stood, this phenotype also emphasizes the importance two subunits in rat superior cervical ganglion (SCG) of Kv1 channels in regulating neuronal excitability. cells, which express both Kv2.1 and Kv2.2, or in HEK-293 cells transfected with cDNAs encoding both Kv1 channels in axons subunits. However, Blaine and Ribera’s studies using a dominant negative Kv2.2 subunit suggest that the two Another feature of Kv1 channels of considerable inter- Kv2 proteins are capable of associating with each other. est is their localization in axons (Figure 3), where they are concentrated in specific microdomains. The T1 Kv2 subunits do heteromultimerize with subunits of domain( Figure s 1 and 2)hasbeenfoundtobeessen-the Kv5, Kv6, Kv8, and Kv9 subfamilies, which, as mentioned previously, are silent pore-forming subunits tial for the axonal targeting of Kv1 proteins. This domain is also the major site of association between that do not form conducting channels by themselves. Kv1 pore-forming and Kvb subunits, and it has been These associations change the voltage dependence b and kinetics of the channels (Table 1). For example, shown that one of these, Kv 2, is important for the targeting of Kv1 channels to the axon. This function co-expression of Kv9.1 with Kv2.1 in Xenopus oocytes depends on its ability to associate with the microtu- slows the rate of activation, causes a hyperpolarizing bule plus-end tracking protein EB1. shift in the voltage dependence of activation and inac- tivation, and changes sensitivity to tetraethylammo- Kv1.1 and Kv1.2 channels are concentrated in a distal part of the axon initial segment, where they nium (TEA). co-localize with ankyrin G and may contribute to Kv2 channels mediate the delayed rectifier regulating action potential initiation (see Figure 6). current IK Kv1 channels are also prominent in presynaptic term- inals, where they might be specifically localized to the Kv2 channels have a low sensitivity to 4-AP (Table 1). preterminal axon. They reduce the excitability of They are blocked by extracellular, 10–20 mM TEA the nerve terminal, thus preventing aberrant firing and are thought to mediate the ‘TEA-sensitive, þ at the terminal (produced by reflection of the action 4-AP-insensitive’ delayed rectifier K current recorded potential from the terminal to the axon) and, hence, in many types of neurons known as I . K aberrant transmitter release. However, in two cases in In heterologous expression systems, Kv2 channels which it has been investigated, the calyx of Held can display different voltage-dependence and kinetic terminal in the auditory brain stem and the terminals properties, including the degree of inactivation, of cortical GABAergic interneurons, the Kv1 current depending on which silent pore-forming subunits
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414 Voltage Gated Potassium Channels: Structure and Function of Kv1 to Kv9 Subfamilies
Figure 3 Contrasting expression patterns of Kv1 and Kv2.1 subunits in the hippocampal formation. In contrast to Kv2.1, Kv1 protein expression is predominantly observed outside the layers containing neuronal somata. Lesioning studies indicate that the observed staining is predominantly associated with local and projecting axons and nerve terminals. The patterns of expression of each Kv1 protein are specific, but there is significant overlap between different subunits. Reproduced from Rhodes KJ, Strassle BW, Monaghan MM, et al. þ (1997) Association and colocalization of the Kvbeta1 and Kvbeta2 beta-subunits with Kv1 alpha-subunits in mammalian brain K channel complexes. Journal of Neuroscience 17: 8246–8258.
form part of the channel complex (Table 1). However, There is also little knowledge about the functional the molecular composition of Kv2 native channel roles of these currents in nerve cells. In one study, complexes and its relationship to IK diversity in neu- it was suggested that because these channels acti- rons and other cell types remain to be determined. vate and deactivate slowly compared to other KvF
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Voltage Gated Potassium Channels: Structure and Function of Kv1 to Kv9 Subfamilies 415 channels, they do not contribute to the repolarization splicing, resulting in the generation of more than ten of single action potentials in cortical pyramidal cells Kv3 isoforms with different intracellular C-terminal þ but instead regulate excitability and Ca2 influx dur- sequences. In heterologous expression systems, Kv3 ing repetitive firing. However, Malin and Nerbonne proteins express fast-activating voltage-gated chan- found that elimination of Kv2 channels in tonic firing nels with unique properties. Compared to the cur- sympathetic neurons increased spike duration. The rents expressed by other KvF subunits, Kv3 currents channels have also been implicated in mediating apo- become apparent at more depolarized potentials ptosis in neurons and are potential therapeutic targets (more positive than 20 to 10 mV; Table 1)and for diabetes due to their prominent expression and deactivate very quickly upon repolarization. The activity in pancreatic b cells. rightward shifted voltage dependence and fast deacti- vation rates of Kv3 channels are likely related proper-
Modulation of Kv2.1 channels ties, probably reflecting instability of the channel’s open state at voltages near the resting potential. Kv2.1 channels are found in high-density clusters in In heterologous expression systems, Kv3.1 and the somata and proximal dendrites, whereas Kv2.2 Kv3.2 subunits mediate slowly inactivating delayed subunits typically present diffuse localization in rectifier-type currents, whereas Kv3.4 proteins pro- somata and neuropil. Kv2.1 clusters are organized duce fast-inactivating A-type currents. In Xenopus in specific subcellular patterns, such as opposite oocytes, Kv3.3 currents are inactivating with time astrocytic processes or inhibitory synapses in cortex constants on the order of tens of milliseconds, but and hippocampus and opposed to cholinergic in mammalian cell lines the inactivation of Kv3.3 synapses on spinal motor neurons. The mechanisms currents is slow and variable. The reason for this of clustering of Kv2.1 channels have been the subject discrepancy is unclear; it has been suggested that it of intense investigation. might be the result of differential usage of a starting Kv2.1 channels are extensively phosphorylated methionine preceding or following an N-inactivation when expressed in HEK 293 cells and in neurons. The domain. Differences in the posttranslational modula- phosphorylation state of Kv2.1 subunits influences tion of Kv3.3 proteins in these two heterologous channel properties, including localization and voltage expression systems could also explain the differences dependence. Furthermore, phosphorylation, localiza- in inactivating properties. Indeed, the degree of inac- tion, and channel properties are dynamically regulated tivation of Kv3.3 and Kv3.4 currents in Xenopus by neuronal activity. Following kainate-induced sei- oocytes is affected by oxidation and protein kinase zures inmice, Kv2.1 channels in pyramidal neuron C (PKC)-mediated phosphorylation. membranes were found to be dephosphorylated rela- Little is known about the function of the alterna- tive to control animals and no longer clustered. In tively spliced C-termini. In the cases in which it has culturedhippocampal pyramidal neurons, glutamate been explored, the currents expressed in heterologous exposure also caused dephosphorylation of Kv2.1 sub- expression systems by the isoforms of each Kv3 gene units, continuous localization (as opposed to clus- are very similar. Preliminary studies suggest that the tered), and a hyperpolarizing shift in the voltage C-termini may confer isoform-specific regulation by dependence of IK. Similar modulations of Kv2.1 second messenger signaling systems and targeting to expression and activity were found following hypoxia distinct neuronal compartments. and chemical ischemia in vivo and in vitro and cholin- ergic stimulation in vitro. Hyperpolarizing shifts of voltage dependence, as observed concomitant with Functional roles of Kv3 channels dephosphorylation, would cause an increase in IK, Three of the four known Kv3 genes (Kv3.1–Kv3.3) which inturn is expected to decrease membrane excit- are prominently expressed in specific neuronal popu- ability. Considering their strong and widespread lations throughout the CNS (Figure 4). Kv3.4 tran- expression, dephosphorylation of Kv2.1 subunits may scripts are weakly expressed in a few neuronal types be an effective and widespread homeostatic mechanism in the brain, usually in neurons also expressing other by which neurons are able to alter excitability in Kv3 genes (hippocampal granule cells, cerebellar Pur- response to their chemical environment. kinje cells, and neurons in the pontine nucleus), whereas they are much more abundant in skeletal muscle and sympathetic neurons. Nevertheless, Kv3 (Shaw) Subfamily Kv3.4 proteins might be important components of There are four known Kv3 genes in mammals – Kv3 channels in some neurons, even when expressed Kv3.1–Kv3.4. In contrast to the other Kv subfamilies, at low levels, since a single Kv3.4 subunit is capable the four Kv3 genes undergo extensive alternative of enabling fast-inactivating properties to a Kv3
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416 Voltage Gated Potassium Channels: Structure and Function of Kv1 to Kv9 Subfamilies
Hippocampus Hippocampus Neocortex Dentate gyrus Superior colliculus Neocortex Dentate gyrus Superior colliculus Mitral cell layer Inferior colliculus Granule cell layer Inferior colliculus Basket cells
V V Olfactory Oltactory bulb bulb Rt Striatum Rt Striatum VP VP Dchn Thalamus Dchn Thalamus Midbrain Midbrain Ve DCn GP Ve DCn Gp R R Vchn M5 Cerebellum Vchn M5 Cerebellum Hindbrain Hindbrain ZI ZI LL LL RtTg RtTg Pn 7 Subthalamic nucleus Pn 7 Subthalamic nucleus Substantia nigra Substantia nigra reticulata LSO MNTB reticulata LSO MNTB Kv3.1 Kv3.2
Hippocampus Neocortex Dentate gyrus Neocortex Hippocampus Dentate gyrus Superior colliculus Superior colliculus Mitral cell layer Inferior colliculus Granule cell layer Inferior colliculus Purkinje cell layer Molecular cell layer Purkinje cell layer
V Oltactory V Olfactory bulb Striatum bulb Striatum Rt Rt VP Dchn VP DChn Thalamus Midbrain Thalamus Midbrain GP Ve DCn GP Ve DCn R Vchn R VChn M5 Cerebellum M5 Cerebellum Hindbrain Hindbrain ZI LL ZI RtTg 7 LL RtTg Subthalamic nucleus Pn Subthalamic nucleus Pn 7 Substantia nigra Substantia nigra reticulata LSO MNTB reticulata LSO MNTB Kv3.3 Kv3.4 Figure 4 Specific but overlapping expression of Kv3 mRNAs in rodent brain. Diagrams illustrating the patterns of expression of Kv3 mRNAs obtained using in situ hybridization by Weiser et al. Darkness indicates level of expression. Reproduced from Rudy B, Chow A, Lau D, et al. (1999) Contributions of Kv3 channels to neuronal excitability. Annals of the New York Academy of Sciences 868: 304–343.
tetrameric channel. In skeletal muscle, Kv3.4 subu- non-Kv3 TEA-sensitive channels (dendrotoxin, char- nits assemble with MinK-related peptide 2 (MiRP2) ybdotoxin or iberotoxin, and linopirdine, respectively) to form subthreshold, voltage-gated potassium chan- can be used to inhibit these other channels and isolate nels that regulate the resting potential of the muscle Kv3 currents or Kv3-mediated effects. However, cell. An R83H missense mutation in MiRP2 that caution should be exercised in pursuing this method diminished the effects of MiRP2 on Kv3.4 has been since 1 mM TEA could block a significant amount of associated with a form of periodic paralysis. the current mediated by channels with a higher IC50 There are no specific blockers of Kv3 channels that for TEA (e.g., Kv2s) if they are very abundant in a can be used to study Kv3 currents in native cells and particular preparation. to investigate their functional roles. BDS toxins The positively shifted voltage dependence of acti- (‘blood depressing substance’) from the sea anemone vation and fast activation/deactivation kinetics of Anemonia sulcata were initially reported to specifi- Kv3 channels bestow these channels with the ability cally block Kv3.4 channels but were later shown to to efficiently and specifically accelerate the repolari- block other Kv3 channels with similar affinity. These zation of the action potential. Kv3 currents are acti- toxins are gating modifiers that shift the voltage vated during the repolarizing phase of the action dependence of the channels in the depolarizing direc- potential and are quickly deactivated following the tion. They tend to produce only partial channel block spike. Hence, when present in sufficient amounts, at physiological membrane potentials and modify Kv3 channels facilitate action potential repolariza- channel properties. Typically, Kv3 currents have been tion and dictate action potential duration without þ isolated using the classical K channel blockers TEA significantly compromising action potential thresh- þ and 4-AP. These are nonspecific K channel blockers; old, rise time, or magnitude and, more important, however, Kv3 channels are very sensitive to these drugs without contributing repolarizing current that and hence can be useful to isolate native Kv3 currents. would increase the duration of the refractory period þ In particular, low ( 1 mM) TEA blocks Kv3 channels (in contrast to voltage-gated K channels activating nearly completely, as well as Kv1.1 homomultimeric more negatively and deactivating more slowly). þ þ channels, BK Ca2 -activated K channels, and Kv7.2 Kv3 channels are particularly prominent in neu- (KCNQ2) channels. Specific toxins that block these rons that have the ability to fire sustained trains of
Encyclopedia of Neuroscience (2009), vol. 10, pp. 397-425
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Voltage Gated Potassium Channels: Structure and Function of Kv1 to Kv9 Subfamilies 417 action potentials at high frequency or to follow high- in motor nerve terminals, and in cerebellar parallel frequency stimulation (Table 1), and they have been fiber terminals. In these synapses, Kv3 channels are shown to facilitate high-frequency firing in cortical key determinants of the repolarization of the local fast-spiking GABAergic interneurons, cerebellar Pur- action potential, keeping action potentials brief, limit- 2þ kinje cells, and neurons in the subthalamic nucleus, ing Ca influx and, hence, neurotransmitter release globus pallidus, and auditory brain stem. This role is probability. As a result of these effects, Kv3 channels in likely the result of their function in spike repolariza- presynaptic terminals contribute to the short-term tion. By increasing the rate of spike repolarization dynamics of synaptic contacts and to maintaining the and keeping action potentials brief, Kv3 currents speed and fidelity of synaptic transmission. þ reduce the amount of Na channel inactivation that occurs during the action potential and minimize the Mutations in Kv3.3 channels cause spinocerebellar þ ataxia activation of K channels with slow kinetics. More- over, the large, fast afterhyperpolarization produced Mutations in the human Kv3.3 gene (KCNC3) have þ by the Kv3 current can speed up recovery from Na been identified as the cause of a spinocerebellar channel inactivation and Kv3 channel deactivation. ataxia (SCA13), a disease that can also include cogni- þ By accelerating the recovery of Na channel inactiva- tive defects, suggesting cerebellar and extracerebellar tion and by deactivating quickly, Kv3 currents effi- dysfunction. Two missense mutations have been ciently restore resting conditions and prepare the described; both mutations are likely to perturb the membrane for a second spike soon after the first role of Kv3.3 channels in the repolarization of action spike, thus minimizing the duration of the refractory potentials in Purkinje cells (and other neurons) and period and allowing high-frequency firing. It has been change their output characteristics. suggested that by regulating the ability to follow Knockout mice have been generated for the three high-frequency stimuli in auditory neurons in the Kv3 genes that are prominently expressed in CNS neu- brain stem, these channels contribute to preserving rons (Kv3.1–Kv3.3). Kv3.1 and Kv3.3 knockout mice the fidelity and timing of firing codes and thus the show alterations in motor behavior,including increased computation of sound features, such as frequency, locomotor activity and sleep loss in Kv3.1 knockout intensity, and localization in space. mice; impaired gait and reduced motor performance
Kv3 gene products are also found in neurons that associated with abnormal Purkinje cell discharges and are not known to fire at high frequencies, such as abnormal olivocerebellar system properties in Kv3.3 magnocellular neurosecretory neurons and starburst knockout mice; and, in the case of the Kv3.1 and cells in the retina, suggesting that Kv3 channels may Kv3.3 double mutant, severe ataxia, tremor,and myoc- have other physiological roles. Some of these func- lonus. Kv3.2 knockout mice have altered EEG tions of Kv3 channels may still be related to their rhythms, increased cortical excitability, and enhanced ability to specifically maximize fast action potential seizure susceptibility, perhaps resulting from altera- repolarization and the consequences of this function: tions in GABAergic control of cortical structures. brief action potentials with quick restoration of mem- brane properties following activity and limiting cal- The Kv4 (Shal) Subfamily cium entry. In starburst neurons, which normally do not spike, it has been proposed that Kv3 channels There are three Kv4 genes in mammals: Kv4.1– provide a voltage-dependent shunt that limits the Kv4.3. The Kv4.1 and Kv4.2 genes produce a single amplitude of neuronal depolarization and might be product each, but the Kv4.3 gene encodes for two critical to the ability of these cells to mediate inhibi- splice variants via alternative splicing: Kv4.3S and tion of ganglion cells, which depends on the direction Kv4.3L (short and long; Table 1). Two of these of movement of visual stimuli. genes, Kv4.2 and Kv4.3, are prominently expressed
in the rodent CNS. Kv4.1 is expressed very weakly Kv3 channels and neurotransmitter release and only in a few neuronal populations, such as the In addition to their localization in neuronal somata, auxiliary olfactory bulb, granule cells of the olfactory
Kv3 channels are also prominently expressed in axons bulb, hippocampus, dentate gyrus, and cerebellar and presynaptic terminals of several neuronal popula- cortex, and possibly in Purkinje cells. In contrast to tions, suggesting roles in regulating neurotransmitter the Kv1 and Kv3 subfamilies, for which there is exten- release (Figure 6). This function has been investigated sive overlap expression of multiple subfamily members in the basket terminals of fast-spiking interneurons in in the same neurons, in the case of Kv4.2 and Kv4.3 the cerebral cortex, in the calyx of Held (the large transcripts, there is a differential, and sometimes recip- presynaptic terminals from the ventral cochlear nucleus rocal, pattern of expression, yet there is overlap expres- bushy cells innervating the neurons in the MNTB), sion in several neuronal populations (Figure 5).
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418 Voltage Gated Potassium Channels: Structure and Function of Kv1 to Kv9 Subfamilies
Figure 5 Pattern of expression of Kv4.2 and Kv4.3 mRNAs in rat brain. Kv4.2 and Kv4.3 gene expression overlaps in certain areas, but in others expression of one of the two predominates (e.g., Kv4.2 in the striatum, hippocampal CA1 area, and cerebellar granule cells in anterior lobules, and Kv4.3 in SNC, superior colliculus, Purkinje cells, and cerebellar granule cells in posterior lobules). Reproduced from þ þ Serodio P and Rudy B (1998) Differential expression of Kv4 K channel subunits mediating subthreshold transient K (A-type) currents in rat brain. Journal of Neurophysiology 79: 1081–1091.
Kv4 proteins produce fast-inactivating channels in pace the frequency of repetitive firing. Furthermore, heterologous expression systems and are believed to Kv4.2 and Kv4.3 proteins are expressed prominently þ underlie fast-inactivating or A-type K currents (IA), in dendrites. Consistent with this pattern, Johnston including the fast transient outward current Ito in and colleagues observed that there is a gradient of ISA cardiac ventricular myocytes, which mediates the channels in CA1 hippocampal pyramidal neurons initial repolarization of the action potential and is with maximum density in distal dendrites. These den- considered a target for arrhythmia treatment, as dritic channels regulate action potential backpropa- well as most of the subthreshold operating somato- gation into the dendritic tree, the integration of þ dendritic A-type K current in mammalian neurons synaptic inputs, and the establishment of long-term (ISA). In neurons, the rapid, transient activation of potentiation (LTP). Utilizing Kv4.2 knockout mice, it these channels in the subthreshold range of mem- has been confirmed that these functions are mediated brane potentials causes delayed excitation, influences by a Kv4.2-dependent I . SA spike repolarization, and determines the duration of Kv channels use novel inactivation mechanisms the interspike interval. The currents are essential in 4 regulating excitability in many neuronal types. By Kv4 channels are characterized by having fast in- regulating the duration of interspike interval, they activation and fast recovery from inactivation. In
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Voltage Gated Potassium Channels: Structure and Function of Kv1 to Kv9 Subfamilies 419
Figure 6 Neuronal Kv proteins are localized to specific membrane microdomains. (a) Kv1.1 (red) in the juxtaparanodal region of myelinated axons. Green, Na+ channels at the node Ranvier; blue, NCP1 at the paranode. (b) Kv1.2 in the axon initial segment of cortical pyramidal neurons (arrows). The cell body is indicated by an asterisk. (c) Kv3.2 in the somatic membrane of a cortical interneuron (asterisk) and the pericomatic (basket) terminals contacting a pyramidal cell. (d) Kv3.1 proteins in the calyx of Held terminal on an MNTb neuron and Kv1.2 in the preterminal axon. (a) Reproduced from Bhat MA, Rias JC, Lu Y, et al. (2001) Axon–glia interactions and the domain organization of myelinated axons requires neurexin iv/Caspr/Paranodin. Neuron 30: 369–383. (b) Reproduced from Inda MC, DeFelipe J, and Mun˜oz A (2006) Voltage-gated ion channels in the axon initial segment of human cortical pyramidal cells and their relationship with chandelier cells. Proceedings of the National Academy of Sciences of the United States of America 103: 2920–2925. (+) (c) Reproduced from Chaw A, Erisir A, Farb C, et al. (1999) K channel expression distinguishes subpopulations of parvalbumin- and somatostatin-containing neocortical interneurons. Journal of Neuroscience 19: 9332–9345. (d) Reproduced from Dodson PD and Forsythe ID + (2004) Presynaptic K channels: Electrifying regulators of synaptic terminal excitability. Trends in Neurosciences 27: 210–217.
þ contrast to most voltage-gated K channels, in which are poorly understood and do not seem to simply open-state inactivation predominates, Kv4 channels conform to the classical N- or P/C-type inactivation seem toinactivate preferentially from closed states. described previously. This implies that modest membrane depolarizations The fast recovery from inactivation characteristic that may not open the channels can render them of Kv4 channels is also an essential feature of these unable to open in response to a subsequent stronger channels given their role in repetitively firing cardiac membrane depolarization. This can result in cumula- and neuronal cells (Table 1). The mechanisms under- tive inactivation upon repetitive stimulation. More- lying this fast recovery are not understood. over, the equilibrium between the open state and a pre-open activated state does not favor residence in Auxiliary subunits the open states even during depolarization. Therefore preferential closed-state inactivation produces most of Several proteins that associate with Kv4 proteins have the inactivation that occurs during a depolarizing pulse been identified, including KChIPs (for Kv channel- and the transient character of the Kv4 current. The interacting proteins), which are members of the neu- þ molecular mechanisms of inactivation of Kv4 channels ronal calcium sensor family of cytosolic Ca2 -binding
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420 Voltage Gated Potassium Channels: Structure and Function of Kv1 to Kv9 Subfamilies
EF-hand proteins, and a family of single-pass integral DPPX and DPP10 are related to DPPIV or CD26, membrane glycoproteins related to dipeptidyl amino- a cell adhesion protein with dipeptidyl-aminopepti- peptidases, known as DPPX (or DPP6) and DPP10. dase activity that has important roles in T cell acti- KChIPs bind to the N-terminal region and the T1 vation, metabolism of peptide hormones, and cell domain of Kv4 proteins; facilitate the trafficking, adhesion. This raises the intriguing possibility that subunit assembly, and surface expression of channel DPP proteins may confer targeting or cell adhesion complexes; and modify the electrophysiological prop- properties to Kv4 channels through their homologous erties of Kv4 channels, which inactivate more slowly extracellular domains, which is reminiscent of the þ and recover from inactivation with faster kinetics in cell adhesion properties conferred on Na channels the presence of KChIPs. There are four known KChIP by the extracellular immunoglobulin-like domain of genes (KChIP1–4). All KChIPs exert similar effects on their b subunits.
Kv4 channels except for the alternative spliced ver- sion KChIP4a: Kv4 channels containing KChIP4a Modulation of Kv4 channel function by lack fast inactivation. The effects of KChIPs on inac- phosphorylation tivation are likely mediated by the sequestration of the N-terminus of the Kv4 proteins in a groove on the Kv4.2 channels in hippocampal neurons are modu- surfaceof the KChIP molecule. lated by extracellular signal-regulated kinase (ERK)– mitogen-activated protein kinase (MAPK) and by DPPX and DPP10 (DPPs) belong to a family of dipeptidyl-aminopeptidase enzymes that have amino protein kinase A (PKA) and PKC. Activation of acid replacements in the catalytic active site and lack these signaling systems reduces channel activity by enzymatic activity. Instead, they seem to have evolved producing an approximately15 mV depolarizing to function as channel-associated proteins. The DPPX shift in the voltage dependence of activation of the and DPP10 genes produce several N-terminal spliced ISA. It is possible that the effects of PKA and PKC isoforms. Products of each gene share the same puta- activation are mediated by a common downstream tive transmembrane domain – a long C-terminal mechanism, the activation of ERK, since blockers of extracellular domain with an hydrolase fold and a MEK, the kinase responsible for the activation of b-propeller (Figure 2b) – but are divergent in the ERK, block ISA modulation by reagents that increase PKA and PKC activity. These modulations have con- short intracellular N-terminal sequence. They increase the rate of inactivation of Kv4 currents, con- siderable physiological significance. In hippocampal siderably decrease the time required for the currents neurons, a Rap1-mediated coupling of cAMP and to reach a maximum (time to peak), and increase the p42/44MAPK participates in the regulation of the rate of recovery from inactivation. In addition, they excitability of pyramidal cells, the early and late produce large negative shifts in the conductance– phases of LTP, and the storage of spatial memory. voltage relation and in the voltage dependence of These effects are mediated at least in part by modula- steady-state inactivation. Furthermore, like KChIPs, tion of Kv4.2 activity. DPPs increase the trafficking of Kv4 proteins to the Furthermore, it has been observed that in spinal cell surface, contributing to the major increase in cord dorsal horn neurons, ISA is also modulated by ERKs, mediating central sensitization during inflam- current magnitude observed in the presence of these auxiliary subunits. In addition, DPPX increases the matory pain. In Kv4.2 knockout mice, ISA in dorsal single channel conductance of Kv4 channels by 50%, horn neurons is absent, and their excitability is a factor that may also contribute to the observed enhanced. This was accompanied by elevated sensi- increases in total current magnitude. tivity to tactile and thermal stimuli. Moreover, the Antibodies to Kv4 proteins coprecipitate KChIP ERK-mediated modulation of excitability and the and DPPX proteins, suggesting that the native chan- ERK-dependent forms of pain hypersensitivity were nel might be a ternary complex of all three types of absent in Kv4.2 / mice. subunits. Consistent with this view, the currents Kv4 channel function, as well as the trafficking and expressed in heterologous cells by Kv4 proteins in expression of functional channels at the plasma mem- brane, may also be modulated by other signaling the presence of KChIPs and DPPs closely resemble the properties of native channels. As in neuronal ISA pathways. In Xenopus oocytes, phorbol esters pro- channels, heterologously expressed channels contain- duce a potent inhibition of channel activity without ing Kv4 proteins and the auxiliary subunits inactivate shifts in voltage dependence. This is mediated by PKC and recover from inactivation quickly, and they cover activation, but the downstream targets of PKC activ- the range of voltage dependencies seen in vivo. The ity remain to be characterized. On the other hand, diversity of Kv4 and auxiliary subunits contributes to CaMKII phosphorylation of Kv4.2 has been shown ISA diversity in native cells. to be important for the expression of functional
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Voltage Gated Potassium Channels: Structure and Function of Kv1 to Kv9 Subfamilies 421 channels at the cell membrane, both in heterologous domain present in the N-terminus. The SID deter- cells and in hippocampal neurons. mines which Kv7 subunits can assemble to form tet- rameric channels, and it contains two motifs of approximately 30 amino acid residues each exhibit-
Kv7 (KCNQ) Channels ing a high probability for coiled-coil formation known as TCC1 and TCC2 (for tetramerizing There are five genes in this group: KCNQ1–KCNQ5. coiled-coil 1 and 2) with a variable linker region in The proteins encoded by these genes constitute the Kv7 between. subfamily of pore-forming potassium channel subu- Data suggest that the TCC1 domains are required nits. Many publications also use the KCNQ nomencla- to form functional homomeric as well as heteromeric ture for the protein products; however, to be consistent channels, at least for Kv7.2 and Kv7.3, and that the with this and other articles in this encyclopedia, we use TCC2 domains facilitate transport of heteromeric the Kv7 nomenclature when referring to the protein channels to the plasma membrane. products of the KCNQ genes. Kv7 (Kv7.1–Kv7.5) channel proteins are homologous to the Kv proteins F Subunit Assembly of Kv7 Proteins discussed previously (Figure 1) and have important roles in the nervous system as well as in other tissues. The five Kv7 proteins can form functional homomeric Of the 80 potassium channel genes in humans, approx- channels. Heteromultimer formation does occur among Kv7 subunits, but it seems to be restricted to imately 10 are known to underlie human diseases. Four of the five known members of the KCNQ subfamily, certain combinations. For example, Kv7.1, which however, are associated with well-characterized chan- is expressed in the heart but not in the nervous system, nelopathies causing cardiac arrhythmia, epilepsy, and does not associate with other Kv7 proteins. On the other hand, Kv7.3 can associate and form functional hearing loss, highlighting the physiological significance of this group of channels. heteromeric channels with Kv7.2, Kv7.4, or Kv7.5, all of which are expressed in neural tissue. This specificity Structural Features of Kv7 Pore-Forming Subunits depends on the C-terminal SID described previously.
þ The Kv7 subfamily of voltage-gated K channel genes This domain is sufficient to transfer assembly proper- þ encodes a group of K channel pore-forming sub- ties between Kv7.3 and Kv7.1 since Kv7.1 chimeras containing Kv7.3 SID fragments acquire the broad units with structural similarity to the KvF subunits assembly properties of Kv7.3. (Figure 1), containing six membrane spanning domains (S1–S6), a positively charged S4 domain that acts as a In native cells, Kv7.1 subunit tetramers are found in association with KCNE accessory proteins such voltage sensor, and a single pore-forming (P) loop with þ as KCNE1 (MinK) and KCNE3. Kv7.2 and Kv7.3 the K channel signature sequence that forms the selec- tivity filter of the channel’s pore. In contrast to the Kv proteins can also co-assemble with KCNE proteins. F subfamilies, the number of positively charged residues Expression and Function of Kv7 Channels: in the S4 domain varies among Kv7 proteins. Kv7.1 The ‘M’ Current has four, whereas Kv7.2–Kv7.5 have six. Further- more, the degree of overall sequence similarity between Expression of Kv7 channels in heterologous systems þ different Kv7 proteins is less than that observed yields an outwardly rectifying voltage-dependent K within Kv1–Kv4 pore-forming subunits (as illustrated current with slow kinetics of activation (in the range by the length of the Kv7 branches in the dendrogram in of hundreds of milliseconds to seconds) and deactiva-
Figure 1). tion and little or no inactivation. There is appreciable It is expected that the Kv7 channel complex is a activation of the currents at voltages more positive tetramer of Kv7 proteins with a structure resembling than 60 mV; hence, Kv7-mediated currents are ‘sub- those shown for Kv1.2 and Kv4s in Figure 2. threshold operating’ in that the greatest influence of In comparison to most of the Kv proteins discussed these currents is predicted to be in the range between previously, Kv7 subunits have very long intracellular resting membrane potential and the voltage threshold
C-terminal tails, particularly Kv7.2 and Kv7.5. for action potential generation. The C-terminal tail contains a highly conserved Comparison of the biophysical and pharmacologi- domain known as the ‘A domain.’ This domain and cal properties (including moderate TEA sensitivity, þ a less conserved sequence that follows it form a sub- inhibition by muscarine, sensitivity to Ba2 blockade, unit interaction domain (SID) involved in subunit- and blockade by both XE991 and linopirdine) of specific assembly among Kv7 proteins. This feature Kv7.2 and Kv7.3 heteromeric channels in heterolo- distinguishes these proteins from the KvF subunits, in gous expression systems with the so-called ‘M’ which subunit assembly depends largely on the T1 current in sympathetic neurons led to the conclusion
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422 Voltage Gated Potassium Channels: Structure and Function of Kv1 to Kv9 Subfamilies that Kv7.2 and Kv7.3 heteromeric channels mediate subunit KCNE1, it forms the channels mediating a this current. current known as IKs, which is important in the repo- The M current (IM) was discovered by Paul Adams larization of cardiac action potentials. It is also pres- and David Brown in sympathetic neurons, and it was ent in a variety of transport epithelia, including the later found to be present in many neurons, including stria vascularis of the inner ear, intestinal crypt cells, sensory peripheral neurons as well as neurons in the and the proximal tubule epithelium of the kidney.
CNS. IM is believed to be one of the most important This pattern of expression rules out this subunit as a currents modulating the subthreshold excitability of contributor to M-type channels in neurons. Kv7.4 is mammalian neurons. IM exhibits voltage dependence found in the nervous system, but it has a more and becomes significant above 60 mV. Hence, the restricted pattern of expression than other neural M current is operative in the subthreshold range of Kv7 subunits, with its expression being limited to membrane potentials, a feature rendering it central in the inner ear and central auditory nuclei in the brain the control of neuronal excitability. Because it does stem (Table 1). This limited distribution indicates not inactivate, or it inactivates extremely slowly and that this subunit likely contributes to IM only in this þ incompletely, it contributes K current during long part of the brain. On the other hand, Kv7.5 is widely depolarizations and leads to substantial steady-state expressed in brain, often overlapping with Kv7.2 and conductance at depolarized potentials. Therefore, IM Kv7.3, and may therefore, either in its homomulti- opposes depolarizing signals and drives the mem- meric form or as heteromultimers, generate IM in brane potential towards EK, functions as a ‘brake’ many neurons, potentially adding to the heterogene- on repetitive action potential discharges, and sup- ity of this current. presses responsiveness to synaptic inputs. Classically, the M currents have been considered to
IM was discovered as the current in sympathetic lack inactivation, and the only Kv7 subunit for which neurons that is inhibited by activation of musca- inactivation is widely recognized is Kv7.1. Nonethe- rinic receptors, mediating muscarinic excitation of less, it has been found that homomeric channels con- these neurons which releases the cell from the control taining Kv7.4 and Kv7.5 subunits (but not Kv7.2) of excitability exerted by IM. This current was expressed heterologously can undergo inactivation. termed M because of this muscarinic modulation. This inactivation is voltage dependent and develops
Subsequent studies have shown that IM is modulated slowly with time constants of several seconds. How- in a similar manner by other neurotransmitters (e.g., ever, it has an impact on the magnitude of the steady serotonin, glutamate, and histamine) as well as several current at voltages in the resting membrane potential neuropeptides (bradykinin, angiotensin, substance P, range (the current is reduced more than 30% at these and opioid) acting through G-protein-coupled recep- voltages), indicating that this mechanism of regula- tors. These modulations, providing additional power- tion could be of physiological significance. Impor- ful means of physiologically modulating neuronal tantly, it was also shown that BMS-204352, a excitability, have been observed in both peripheral selective Kv7 channel opener, exerts its effect, at and CNS neurons. least partially, by abolishing the inactivation of these Given their abundant, widespread, and largely channels. þ overlapping expression in the nervous system Some members of the voltage-gated K channel (Table 1), Kv7.2 and Kv7.3 (probably often as family EAG express currents that activate slowly components of heteromeric channels containing and do not inactivate, as is the case of typical both subunits) are likely mediators of I in many M currents. Therefore, the currents mediated by M central and peripheral neurons. However, all Kv7 these EAG channels have been referred to as M-like. channels expressed heterologously are able to form EAG channels are prominently expressed in specific functional homomultimeric channels that express neuronal populations, especially in the forebrain, and þ currents with electrophysiological and pharmaco- may contribute M-like K currents in neurons. logical characteristics of M-type currents. They all Results from immunolocalization of Kv7.2 and express currents with similar time and voltage Kv7.3 proteins suggest that the currents mediated by dependence, they are all inhibited by the IM blocker Kv7 channels may have additional functions besides linopirdine, and they are similarly inhibited by neu- mediating the IM recorded in neuronal cell bodies. rotransmitters. These include localization at the axon initial segment Among the Kv7 proteins, Kv7.1 is the only member in a variety of neurons and at the node of Ranvier in not detected in the nervous system (Table 1). Kv7.1 is myelinated axons. Furthermore, Kv7.2 is expressed in present in the heart (found in atrial and ventricular the mossy fibers of the hippocampus, and there is myocytes), where, in combination with the accessory pharmacological evidence for the presence of Kv7
Encyclopedia of Neuroscience (2009), vol. 10, pp. 397-425
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Voltage Gated Potassium Channels: Structure and Function of Kv1 to Kv9 Subfamilies 423 currents in the Schaffer collaterals, where they appear are critically maintained within certain levels in early to regulate transmitter release. infancy. Why seizure activity disappears in most patients after a few weeks is not clear. Perhaps the Diseases Associated with Kv7 Channels maturation of inhibitory GABAergic systems later in
We briefly describe the diseases associated with muta- life allows for better control of the increased excit- tions in the genes encoding Kv7 proteins. ability resulting from KCNQ mutations. Deletion of Kcnq2 in mice is lethal. Homozygous
KCNQ1 and LQTS/JLNS Long QT syndromes animals die a few hours after birth due to breathing (LQTS) are inherited cardiac disorders caused by problems. Heterozygous animals develop normally mutations in the genes that encode sodium or potas- and lack spontaneous epileptic activity, but they have an increased susceptibility to pentylenetetra- sium transmembrane ion channel proteins, character- ized by arrhythmias which are often fatal. More than zole-induced seizures. On the other hand, transgenic 200 mutations, in at least six genes, have been found mice that conditionally express dominant negative Kv7.2 subunits in brain have spontaneous seizures, in these patients. Mutations in the KCNQ1 gene are responsible for the most common form of the disease behavioral hyperactivity, increased neuronal excit- (LQT1), accounting for more than 50% of the cases. ability consistent with a reduced M current, and mor- An autosomal dominant form of LQT1, known as phological changes in the hippocampus. Temporal
Romano–Ward syndrome, is the result of dominant control of expression of the transgene showed that negative mutations; on the other hand, the Jervell and Kv7 channel activity is critical to the development of Lange-Nielsen syndrome (JLNS) is the recessive form normal hippocampal morphology during the first of the disease and is associated with deafness, result- postnatal weeks. þ ing from failure of K transport into the endolymph in the cochlea. These phenotypes have been repro- KCNQ4 and inherited deafness KCNQ4 maps to the DFNA2 locus in human chromosome 1p34, one duced in knockout mice. of more than 30 loci for dominant inherited deafness, KCNQ2 and KCNQ3 in neonatal epilepsy Given and DFNA2 patients have been found to have muta- the extensive overlap in expression patterns of tions in the KCNQ4 gene. The mechanism leading to
Kv7.2 and Kv7.3 in brain tissue and the evidence deafness in DFNA2 is different than that causing the that in most neurons the IM channels are heteromeric hearing defect found in JLNS (produced by KCNQ1 channels containing both subunits, it is perhaps not mutations), consistent with the different patterns of surprising that mutations in each gene produce the expression of the two genes in the ear (Table 1). In same phenotype – an autosomal dominant idiopathic DFNA2, hearing loss develops slowly, progressing epilepsy known as benign familial neonatal convul- over decades, probably as a result of degeneration of sions (BFNC). the outer hair cells (OHCs). Although KCNQ4 is also
BFNC is a rare disease characterized by unpro- expressed in sensory hair cells of the vestibular organ, voked partial or generalized clonic convulsions, some- people with DFNA2 have no vestibular symptoms. times with ocular symptoms and apnea. BFNC KCNQ4 is expressed in both inner and outer hair typically begins soon after birth, and remission usu- cells of the inner ear, where the currents may serve ally occurs after 3–10 weeks, although approximately different functions. In OHCs, Kv7 currents are large 15% of patients have seizures later in life. BFNC and constitute the dominant currents at rest and dur- was initially linked to two different loci, 20q13.3 ing depolarization, also representing the principal þ and 8q24, which are now known to contain the exit pathway for K ions entering the cells through KCNQ2 and KCNQ3 potassium channel genes, the transduction channels. In inner hair cells, the respectively. A large number of mutations have been current is relatively small and it influences mainly identified, particularly in KCNQ2, and include mis- resting membrane properties. Loss-of-function muta- sense, frame-shift, and splice-site mutations as well as tions of the KCNQ4 gene, causing hearing loss in a deletion. The functional effects of the mutations humans, also result in OHC degeneration. Similarly, have been explored in heterologous expression sys- KCNQ4 knockout mice or mice carrying KCNQ4 tems, and many of these were not found to have mutations also develop progressive OHC degenera- dominant negative effects, indicating that the domi- tion, which parallels a progressive hearing loss. OHC þ nant inheritance of BFNC is due to haploinsufficiency. degeneration is believed to result from Ca2 -dependent
Interestingly, the reduction of current observed with excitotoxicity produced by use-dependent chronic some of the mutations was rather modest, approxi- depolarization of the cell as a consequence of reduced þ mately 25%, indicating that the levels of the current K current. Interestingly, some investigators have
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424 Voltage Gated Potassium Channels: Structure and Function of Kv1 to Kv9 Subfamilies
þ suggested an association between increased frequency changes in Ca2 , DAG, or IP , and it increases when 3 of age- and job-related deafness and specific KCNQ4 PIP2 levels rise. This result shows that PIP2 depletion polymorphisms. alone without changes in other second messengers is able to fully suppress the current. PIP comprises only 2 approximately 1% of the cell membrane, and it is Modulation of Kv7 Channels found mostly in the inner cell leaflet. Muscarinic
The mechanism of inhibition of IM by neurotransmit- and bradykinin receptor activation have been shown ters has been the subject of intense investigation since to produce large decreases in PIP2 in neuroblastoma the current and its modulation were discovered in 1980. cells and in mammalian cell expression systems – Yet, the mechanism of modulation remained elusive approximately 35% for bradykinin and more than for more than 20 years. Classical second messengers 75% for muscarine within 30–60 s. Experiments known at the time of the discovery of the M current have shown that different Kv7 subunits have very did not seem to be involved. By the early 1990s, it was different affinities for PIP2: Kv7.3 > Kv7.2 > Kv7.4, clear that M-type channel inhibition by neurotransmit- with EC ranging from three to several hundred 50 ters uses G-protein activation, as is the case for other micromolar. This heterogeneity could confer diversity G-protein-coupled receptor (GPCR)-mediated modula- to Kv7-mediated neurotransmitter effects in different tions, and specifically the Gaq subunit (with occasional sites in the nervous system. contribution from G11). Activation of these G-proteins Although regulation of PIP2 levels is likely the main is known to stimulate the activity of the membrane- mechanism of M current inhibition, other molecules associated phospholipase Cb. This enzyme hydrolyses and signaling events are likely to contribute as well þ the membrane phospholipid phosphatidylinositol-4,5- in specific cases. For instance, Ca2 ions inhibit, at bisphosphate (PIP2), leading to the production of inosi- concentrations of approximately 100–200 nM, M tol-1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). channels containing Kv7.2, Kv7.4, and Kv7.5 (but These products are key messengers involved in the sig- not Kv7.1 or Kv7.3) through an interaction with naling mediated by Gq and G11, as well as several other calmodulin. It appears that the inhibition of IM cur- 2þ G proteins. IP3 leads to elevation of intracellular Ca rents by bradykinin in sympathetic neurons is due þ via release from intracellular stores, and DAG activates mainly to Ca2 -dependent block resulting from an 2þ PKC. However, experiments investigating the roles of IP3-mediated increase in intracellular Ca . In these these signaling molecules on the modulation of cells, bradykinin does not produce sufficient deple- M currents produced conflicting results at best. tion of PIP2 to inactivate the channels via this mech- þ A breakthrough occurred in 2002 when Byung-Chang anism because the increase in Ca2 concentration
Suh and Bertil Hille performed experiments that sug- promotes PIP2 synthesis. The reason why the mecha- gested that perhaps it is the depletion of PIP2 from the nism of IM modulation by muscarine in sympathetic membrane and not the products of its hydrolysis that neurons differs from the mechanism of modulation by causes the inhibition of the M-type channels. Suh and bradykinin is that muscarinic receptors are too dis- Hille studied the recovery of the M channels from tant from the IP3 receptors to induce a large release of þ muscarinic inhibition and showed that this process Ca2 . This is in contrast to the closer localization of 2þ requires hydrolysable ATP and is slowed if PIP2 resyn- bradykinin receptors to the intracellular Ca stores. thesis is inhibited with wortmannin, a blocker of PI4K Other signaling pathways may also contribute to kinase, which is an enzyme required for the generation IM inhibition, including PKC, cyclic ADP-ribose, and of PIP . Soon after, Diomedes Logothetis and collea- tyrosine kinases. The action of at least some of these 2 gues showed that Kv7.2 and Kv7.2–Kv7.3 channels in signals on Kv7 channels may converge on the require- inside-out oocyte membrane patches undergo a run- ment of PIP2 for channel activity. For example, since 2þ down that could be recovered by the addition of PIP2. one of the Ca -calmodulin binding sites on the chan-
The rundown could be restored using an antibody nel overlaps a putative PIP2 binding site, Brown and 2þ directed against PIP2 or polylysine to sequester PIP2, colleagues have suggested that Ca binding may providing direct evidence that Kv7 channels require produce channel closure by displacing PIP2.
PIP2 for activity, as had been shown to be the case for At normal resting concentrations of PIP2, M chan- several other ion channels. nels are not fully open, allowing for the possibility of A large body of research now exists supporting the enhancing the resting IM pharmacologically. Enhanc- view that the primary mechanism by which GPCRs ing I should reduce excitability and counteract M inhibit IM is via depletion of membrane-associated convulsions. This is the effect of the drug retigabine. PIP2. Hille and colleagues have used translocatable Retigabine originated from the National Institutes of enzymes to rapidly alter the PIP2 levels. When PIP2 is Health Antiepileptic Drug Development Program. depleted, the Kv7 current declines to zero without The main action of this compound is to shift the
Encyclopedia of Neuroscience (2009), vol. 10, pp. 397-425
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Voltage Gated Potassium Channels: Structure and Function of Kv1 to Kv9 Subfamilies 425 current–voltage curve of Kv7 currents to the left Hille B (1992) Ionic Channels of Excitable Membranes. Sunder-
(although it also increases the maximum opening land, MA: Sinauer. Jentsch TJ (2000) Neuronal KCNQ potassium channels: Physiol- probability) via an interaction of retigabine with resi- ogy and role in disease. Nature Reviews Neuroscience 1(1): dues in the S5 and S6 domains of Kv7 proteins, with a 21–30. tryptophan residue in the S5 domain as the key deter- Jerng HH, Pfaffinger PJ, and Covarrubias M (2004) Molecular minant. This tryptophan is absent from the cardiac physiology and modulation of somatodendritic A-type potas- Kv7.1 channel, which is therefore resistant to retiga- sium channels. Molecular and Cellular Neuroscience 27(4): 343–369. bine action. Retigabine has potent anticonvulsant Johnston D, Christie BR, Frick A, et al. (2003) Active dendrites, activity. It also enhances IM in nociceptive sensory potassium channels and synaptic plasticity. Philosophical neuronsand exerts antinociceptive effects, particu- Transactions of the Royal Society of London Series B: larly against neuropathic pain. No published accounts Biological Sciences 358(1432): 667–674. of retigabine efficacy in the clinical treatment of Kaczmarek LK, Bhattacharjee A, Desai R, et al. (2005) Regulation of the timing of MNTB neurons by short-term and long-term chronic pain exist. However, numerous open-label modulation of potassium channels. Hearing Research 206(1–2): and double-blind controlled trials have shown that 133–145. the close structural analog and Kv7 channel opener Lai HC and Jan LY (2006) The distribution and targeting of neuro- flupirtine is effective in alleviating pain associated nal voltage-gated ion channels. Nature Reviews Neuroscience with a diverse range of etiologies. 7(7): 548–562. Long SB, Campbell EB, and Mackinnon R, (2005) Crystal structure Kv7 channel modulation with retigabine has also of a mammalian voltage-dependent Shaker family K+ channel. been shown to reduce the distonia in a mouse model Science 309: 897–903. of paroxysmal dyskinesia. Substantial effects of reti- Long SB, Campbell EB, and Mackinnon R (2005) Voltage sensor of gabine have also been seen on dopaminergic neuron Kv1.2: structural basis of electromechanical coupling. Science 309: 903–908. firing rate in slice preparations. Misonou H, Mohapatra DP, and Trimmer JS (2005) Kv2.1: þ A voltage-gated K channel critical to dynamic control of neu- See also: Calcium Channel and Calcium-Activated ronal excitability. Neurotoxicology 26(5): 743–752. Potassium Channel Coupling; Inwardly Rectifying Pongs O, Leicher T, Berger M, et al. (1999) Functional and þ Potassium Channels; Ion Channel Localization in Cell molecular aspects of voltage-gated K channel beta sub- Bodies and Dendrites; Large Conductance Calcium- units. Annals of the New York Academy of Sciences 868: Activated Potassium Channels; Potassium Channel 344–355. Robbins J (2001) KCNQ potassium channels: Physiology, patho- Regulation; Two-P-Domain (K2P) Potassium Channels: Leak Conductance Regulators of Excitability; Voltage- physiology, and pharmacology. Pharmacology & Therapeutics
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Further Reading lian brain K+ channel complexes. Journal of Neuroscience 17:
8246–8258. Bezanilla F (2000) The voltage sensor in voltage-dependent ion Rudy B, Chow A, Lau D, et al. (1999) Contributions of Kv3 channels. Physiological Reviews 80(2): 555–592. channels to neuronal excitability. Annals of the New York Birnbaum SG, Varga AW, Yuan LL, et al. (2004) Structure and Academy of Sciences 868: 304–343. þ function of Kv4-family transient potassium channels. Physio- Rudy B and McBain CJ (2001) Kv3 channels: Voltage-gated K logical Reviews 84(3): 803–833. channels designed for high-frequency repetitive firing. Trends in Choe S, Cushman S, Baker KA, and Pfaffinger P (2002) Excitability Neurosciences 24(9): 517–526. is mediated by the T1 domain of the voltage-gated potassium Sheng M and Wyszynski M (1997) Ion channel targeting in neu- channel. Novartis Foundation Symposium 245: 169–175. rons. Bioessays 19(10): 847–853. Coetzee WA, Amarillo Y, Chiu J, et al. (1999) Molecular diversity þ Strop P, Bankovich AJ, Hansen KC, Garcia KC, and Brunger AT of K channels. Annals of the New York Academy of Sciences (2004) Structure of a human A-type potassium channel
868: 233–285. interacting protein DPPX, a member of the dipeptidyl
Delmas P and Brown DA (2005) Pathways modulating neural aminopeptidase family. Journal of Molecular Biology 343: KCNQ/M (Kv7) potassium channels. Nature Reviews Neuro- 1055–1065. science 6(11): 850–862. Wang H, Yan Y, Liu Q, et al., Structural basis for modulation of Doyle DA, MoraisCabral J, Pfuetzner RA, et al. (1998) The struc- + þ Kv4 K channels by auxiliary KChlP subunits. Nature Neurosci- ture of the potassium channel: Molecular basis of K conduc- ence 10: 32–39. tion and selectivity. Science 280(5360): 69–77. Yu FH and Catterall WA (2004) The VGL-chanome: A protein Goldberg EM, Watanabe S, Chang SY, et al. (2005) Specific func- superfamily specialized for electrical signaling and ionic homeo- tions of synaptically localized potassium channels in synaptic stasis. STKE Science’s 253: re15. transmission at the neocortical GABAergic fast-spiking cell syn- apse. Journal of Neuroscience 25(21): 5230–5235. Harvey AL and Robertson B (2004) Dendrotoxins: Structure– Relevant Website activity relationships and effects on potassium ion channels. Current Medicinal Chemistry 11(23): 3065–3072. http://www.informatics.jax.org – Mouse Genome Informatics.
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