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Neuropharmacology 44 (2003) 1–7 www.elsevier.com/locate/neuropharm Review Pharmacology of neuronal background channels Florian Lesage Institut de Pharmacologie ´culaire et Cellulaire, CNRS UMR6097, 660, route des lucioles, Sophia Antipolis, 06560 Valbonne, France

Received 10 May 2002; received in revised form 9 August 2002; accepted 26 September 2002

Abstract

Background or leak conductances are a major determinant of membrane and input resistance, two key components of neuronal excitability. The primary structure of the background K+ channels has been elucidated. They form a family of channels that are molecularly and functionally divergent from the voltage-gated K+ channels and inward rectifier K+ channels. In the nervous system, the main representatives of this family are the TASK and TREK channels. They are relatively insensitive to the broad- spectrum K+ channel blockers (TEA), 4-aminopyridine (4-AP), Cs+, and Ba2+. They display very little time- or voltage-dependence. Open at rest, they are involved in the maintenance of the resting in somatic motoneu- rones, brainstem respiratory and chemoreceptor neurones , and cerebellar granule cells. TASK and TREK channels are also the targets of many physiological stimuli, including intracellular and extracellular pH and temperature variations, hypoxia, bioactive lipids, and modulation. Integration of these different signals has major effects on neuronal excitability. Activation of some of these channels by volatile anaesthetics and by other neuroprotective agents, such as and unsaturated fatty acids, illustrates how the neuronal background K+ conductances are attractive targets for the development of new drugs.  2002 Elsevier Science Ltd. All rights reserved.

Keywords: Leak channels; Resting potential; Excitability

Contents

1. Introduction ...... 1

2. The two-pore- domain K+ channels ...... 2

3. TASK channels in the nervous system ...... 3

4. TREK channels in the nervous system ...... 4

5. Modulation of neuronal background K+ channels by clinically relevant compounds ...... 5

6. Conclusion ...... 6

1. Introduction currents involved in generation, these authors proposed a voltage-insensitive leak current as the The existence of background conductances in neu- basis of the resting membrane potential. Subsequently, rones was originally postulated by Hodgkin and Huxley it was shown that the resting potential in different types (1952). In addition to the voltage-sensitive Na+ and K+ of neurones depended primarily on K+-selective currents showing a relative insensitivity to classical K+ channel blockers (Baker et al., 1987; Jones, 1989; Premkumar et E-mail address: [email protected] (F. Lesage). al., 1990; Shen et al., 1992; Koh et al., 1992; Koyano

0028-3908/03/$ - see front matter  2002 Elsevier Science Ltd. All rights reserved. doi:10.1016/S0028-3908(02)00339-8 2 F. Lesage / Neuropharmacology 44 (2003) 1–7 et al., 1992; Theander et al., 1996). For example, in mye- domains are crucial for the formation of the pore selec- linated nerve, different K+ conductances can be success- tivity filter. Given that K+ subunits with one P domain ively removed by sequential applications of TEA, 4-AP are active as tetramers and that four P domains form the and Cs+; but treated axons still exhibit strong outward K+-selectivity filter (Doyle et al., 1998), it was hypoth- rectification suggesting that residual K+ conductance is esised early that leak K+ channels with two P domains present. The conductance, which is believed to set the were active as dimers. As expected, TWIK1 does form resting potential, is voltage-independent but outwardly dimers (Lesage et al., 1996b). These multimers contain rectifying, as expected from constant field theory (Baker an interchain disulfide bridge. The cysteine residue et al., 1987). This type of current is easily distinguish- involved in this bond is part of the extracellular loop able from the voltage-sensitive inwardly rectifying K+ located between the first membrane-spanning segment currents that play a similar role in cardiac and skeletal (M1) and the first P domain (P1). The predicted structure muscle cells (Hille, 1992). Until recently, neuronal back- of this M1P1 loop is an alpha-helix containing a regular ground currents received only a fraction of the attention occurrence of hydrophobic and charged residues. This that was devoted to the voltage-gated and Ca2+- sensitive profile is typical of interdigitating helices that interact K+ currents, but the recent cloning of a new family of through hydrophobic interactions. The regular occur- K+ channels has permitted a detailed characterisation of rence of hydrophobic and charged residues is conserved the electrophysiological and pharmacological properties, in the M1P1 loops of all the TWIK-related subunits. The and regulation of these currents (for reviews see Lesage cysteine residue and the ability to form covalent disul- and Lazdunski, 2000; Patel and Honore´, 2001). Electro- fide-dridged dimers are also conserved in the majority physiology of the corresponding conductances in vivo, of these subunits (Lesage et al., 2001). A functional in association with in situ hybridization and immunohis- approach has recently demonstrated that TASK1 tochemistry, has revealed a broad distribution of these (although it lacks this cysteine) is also active as a dimer channels in the nervous system. Another major result is (Lopes et al., 2001). In addition, the covalent dimeriz- the tight and specific regulation of these channels by a ation of some of these channels has been confirmed by variety of physical and chemical stimuli, suggesting that Western blot analysis of native (Lesage and precise tuning of their activity is associated with - Lazdunski, 2000; Reyes et al., 2000; Hervieu et al., specific regulation of neuronal activity. 2001). These dimers contain four P domains, two P1 and two P2, supporting the idea that both P domains are functional and are involved in the formation of the ionic 2. The two-pore- domain K+ channels pore. In the leak channels, the first P1 domain can accommodate residues that are never observed in the K+ channels form the largest family of channels. one-P channels and that can suppress the channel activity More than 70 encoding pore-forming subunits when introduced in these channels. The unusual sym- have been identified in the . These sub- metry, resulting from dimerization, probably provides an units are organised into three main families according evolutionary flexibility that is not possible with the to their predicted membrane topology. The two largest tetrameric symmetry of one-P-domain channels. Two-P- families comprise subunits with six or two membrane- domain channels are mainly active as homodimers but spanning segments and one pore (P) domain (Jan and a recent study suggest that TASK1 and TASK3, in parti- Jan, 1997). These subunits assemble as homo- or heterot- cular, are able to form heterodimers (Czirjak and etramers to form active channels belonging to different Enyedi, 2002). functional groups including the extensively characterised Two-P-domain K+ channels are present in all exam- voltage-gated K+ channels, Ca2+-dependent K+ channels, ined tissues. However, each channel has its own profile ATP-sensitive K+ channels, G--coupled K+ chan- of expression giving to each tissue a unique channel nels, and inward rectifiers. The third family of pore-for- combination (Lesage and Lazdunski, 2000; Medhurst et ming subunits was discovered by DNA database mining. al., 2001). In human brain, the most represented two- The first channel to be cloned was TWIK1 (Lesage et al., P-domain K+ channels are TWIK1, KCNK7, TASK1, 1996a), subsequently followed by 13 additional TWIK- TASK3, TREK1, TREK2 and TRAAK (Fig. 1) related channels in human (Fig. 1). The corresponding (Medhurst et al., 2001). TWIK1, KCNK7, TASK3 and genes, designated KCNK1 to 17, are only distantly TRAAK are predominantly expressed in the CNS, related to the other K+ channel genes in evolution whereas TASK1 and TREK2 are equally present in the (Lesage et al., 1996a; Patel and Honore´, 2001; Girard et CNS and peripheral tissues (Medhurst et al., 2001). In al., 2001; Karschin et al., 2001). the brain, each channel displays a unique pattern of The TWIK1-related proteins are 300–500 residues expression with some striking differences between spec- long and share similar hydropathic profiles predicting ies. For example, TASK3, which is nearly exclusively four membrane-spanning segments. The most salient expressed in the cerebellum in human (Medhurst et al., feature is the presence of two P domains per subunit. P 2001), is found more widely in rodent brain with high F. Lesage / Neuropharmacology 44 (2003) 1–7 3

Fig. 1. The two-P-domain K+ channels form different structural and functional subclasses. The dendrogram has been produced by Treeview using a ClustalW alignment of human sequences. levels of expression in cerebellar granule neurones, play only little time- or voltage-dependence. Their acti- somatic motoneurones, raphe nuclei, and neurones of vation and inactivation kinetics are very fast. These cur- locus coeruleus and hypothalamus (Karschin et al., 2001; rents display an outward rectification that can be Talley et al., 2001). Conversely, TREK2, which is approximated by the Goldman–Hodgkin–Katz (GHK) restricted to the granule cell layer in the rodent cerebel- current equation that predicts a curvature of the I–V lum (Talley et al., 2001), is broadly expressed in human relationships in physiological asymmetric K+ conditions. brain, especially in the occipital lobe, putamen and thala- A notable property of TASK channels is their extreme mus (Lesage et al., 2000). Finally, a recent study showed sensitivity to variations in external pH in a narrow an abundant expression of the TASK2 protein in rat physiological range (TASK standing for TWIK-related brain (Gabriel et al., 2002), whereas the messenger for Acid-Sensitive K+ channel). They are inhibited by extra- this channel was barely detected by PCR in human and cellular acidosis with a midpoint of inhibition of 7.3 for mouse brains (Reyes et al., 1998; Medhurst et al., 2001). TASK1, and 6.3 for TASK3 (Lesage and Lazdunski, These differences cannot be exclusively attributed to the 2000; Chapman et al., 2000; Rajan et al., 2000; Kim et variety of techniques used (RT–PCR, Northern blotting, al., 2000). TASK1 and TASK3 are relatively insensitive in situ hybridization, and immunohistochemistry) and to Ba2+,Cs+, TEA, and 4-AP, although TASK1 is could also reflect species-specific adaptations. The specifically and directly blocked by submicromolar con- remainder of this review will focus on TASK and TREK centrations of the endocannabinoid anandamide channels, as they represent the most abundant two-P- (Maingret et al., 2001). domain K+ channels expressed in the CNS. TASK-like currents have been identified in many sites throughout the nervous system, thanks to their unique electrophysiological and pharmacological properties, 3. TASK channels in the nervous system and their sensitivity to pH. They form prominent leak conductances in rat cerebellar granule cells (Millar et al., TASK1 (KCNK3) and TASK3 (KCNK9), together 2000; Maingret et al., 2001), hypoglossal motoneurones, with the non-functional TASK5 (KCNK15) subunits, locus coerelus and serotoninergic raphe neurones (Talley form a subfamily of structurally related channels (Fig. et al., 2000; Washburn et al., 2002; Bayliss et al., 2001). 1). They produce strong basal currents with all the In hypoglossal motoneurones and cerebellar granule characteristics of leak conductances. TASK currents dis- cells, these TASK-like currents are inhibited by different 4 F. Lesage / Neuropharmacology 44 (2003) 1–7

known to stimulate Gq/11-coupled converted into constitutively active channels by intra- receptors (acetylcholine, serotonin, norepinephrine, thyr- cellular acidosis and by elevated temperature. All these otropin-releasing , substance P, and glutamate). channels can be reversibly opened by lipids such as lyso- This neurotransmitter effect is fully reconstituted in phospholipids containing large polar heads (LPA and transfected cells or Xenopus oocytes co-expressing a Gq- LPC), and unsaturated fatty acids including arachidonic coupled and the cloned TASK channel (Millar acid (AA). Finally, these channels are the target of neur- et al., 2000; Talley et al., 2000). Blockade of leak K+ otransmitter modulation. TREK1 and TREK2 are modu- conductances by neurotransmitters is one of the principal lated by Gq-, Gi- and Gs-coupled receptors. Stimulation mechanisms by which neurotransmitters modulate neu- of co-expressed Gq-coupled glutamate receptor mGluR1 ronal excitability (Siegelbaum et al., 1982; Premkumar or the Gs-coupled serotonin receptor 5-HT4sR inhibits et al., 1990; Shen et al., 1992; Koyano et al., 1992), and TREK1 and TREK2 activities, whereas activation of the

TASK channel blockade by neurotransmitters induces Gi-coupled mGluR2 increases these TREK currents (Fig. membrane depolarisation and an increase in the likeli- 2). TREK1 closing is mediated by - hood of action potential discharge. For instance, in mice mediated phosphorylation of Ser333, a residue con- lacking the α6 subunit of GABAA receptor, the tonic served in TREK2, and by protein kinase C although the inhibitory ClϪ conductance mediated by this receptor is corresponding phosphorylation site remains unidentified lacking. However, the amount of excitation needed for (Patel et al., 1998; Lesage et al., 2000). granule cells to emit an action potential in α6-deficient The TREK channels share many pharmacological and mice is similar to that of control mice. This is due to a electrophysiological properties with the Aplysia S-type compensatory over-expression of a TASK conductance channel that, until recently, was the best-characterised in the α6 knock-out mice (Brickley et al., 2001). These background K+ channel (Siegelbaum et al., 1982). Like data suggest that TASK channels participate in the long- TREKs, the S-type channel is time- and voltage- term homeostatic regulation of neuronal excitability. independent, outwardly rectifying and TEA-resistant. TASK currents are also attractive candidates to Like TREKs, it is inhibited by the mediate chemoreception because they are functionally neurotransmitter/cAMP/PKA pathway and activated by expressed in respiratory-related neurones, including air- (Patel et al., 1998). By controlling pre- way motoneurones and putative chemoreceptor neurones synaptic facilitation between sensory and motor neu- of locus coeruleus (Bayliss et al., 2001). Inhibition of rones of the reflex pathway, this channel is involved in TASK currents by extracellular acidosis depolarises and behavioural sensitisation of the gill-withdrawal reflex, increases excitability of these cells, thereby enhancing which is a simple form of learning and memory. Sero- respiratory motoneuronal output. TASK channels are tonin released from interneurones activates PKA, which also present in chemosensitive carotid body cells inhibits the leak S-type conductance in presynaptic ter- (Buckler et al., 2000). Their closing by hypoxia and aci- minals. This induces action potential prolongation, dosis likewise induces membrane depolarisation, initiat- allowing more to flow into the terminal, ulti- ing release and ultimately a reflex increase in mately increasing transmitter release. Given their func- respiration. Modulation of TASK channels, both at the tional properties and their wide distribution in the brain, central and peripheral levels, is expected to contribute the TREK channels may have a similar role in the mam- to the respiratory reflex. malian nervous sytem. Background K+ currents, acti- vated by polyunsaturated fatty acids, have already been recorded in cultured neurones prepared from different 4. TREK channels in the nervous system brain areas that express TREK channels such as hippo- campal, mesencephalic and hypothalamic neurones The TREK (TWIK-related K+ channels) subfamily (Premkumar et al., 1990; Kim et al., 1995) and cerebel- comprises three subunits with related structural and elec- lum granular cells (Lauritzen et al., 2000, Han et al., trophysiological properties (TREK1/KCNK2, in press). TREK2/KCNK10, and TRAAK/KCNK4) (Fig. 1). The expression of TREK1 in cold-sensitive peripheral TREK channels produce baseline currents similar to and central neurones, together with its sharp tempera- TASK currents with a GHK outward rectification in ture-sensitivity, supports a role of this channel in thermo- physiological K+ conditions, and very fast activation and regulatory processes (Maingret et al., 2000). Cold-sensi- deactivation kinetics, as well as a relative insensitivity tive neurones respond to a temperature decrease with to the classical K+ channel blockers. However, whereas bursts of action potentials. This transduction depends on the basal activity of TASK channels is high, TREK a complex interplay among different ion channels activity at rest is low. TREK channels are strongly including leak K+ channels (Viana et al., 2002). The stimulated by increasing the mechanical pressure applied closure of TREK1 may contribute to the depolarisation to the and closed by hypo-osmolarity. that is observed when temperature drops. Additionally, TREK1 and TREK2, but not TRAAK, are Finally, a mechano-gated, fatty acid-activated and F. Lesage / Neuropharmacology 44 (2003) 1–7 5

Fig. 2. This schema summarises the physical and chemical stimuli affecting the activity of TREK and TASK channels. TASK channels have strong basal activities and integrate essentially negative stimuli (in red). TREK channels with low basal activity integrate positive (in green) and negative stimuli. TRAAK has the same regulations than TREK1 and TREK2 save the inhibition by internal acidosis, and the effects of temperature and transmitter receptor activation. In addition, TRAAK is insensitive to PKA phosphorylation, and its activation by riluzole is sustained and not transient as described for TREK1 and TREK2. intracellular acidification-sensitive TREK2-like current of inhalational anaesthetics. In motoneurones, raphe neu- has been recently recorded from rat brain rones and cerebellar granule cells, opening of TASK (Gnatenco et al., 2002). These results suggest that channels probably contributes to anaesthetic-induced TREKs may have role additional roles, such as K+ immobilisation and sedation, whereas in locus coeruleus homeostasis, in non-excitable cells of the brain. it might underlie analgesic and hypnotic effects. In con- trast to the volatile anaesthetics, local anaesthetics including bupivicaine and inhibit two-P- 5. Modulation of neuronal background K+ channels domain K+ channels, particularly the TASK channels by clinically relevant compounds (Kindler et al., 1999; Lesage and Lazdunski, 2000). These agents are believed to inhibit neuronal firing and Background K+ channels in Aplysia sensory neurones conduction through the block of voltage-gated Na+ chan- and in Lymnea pacemaker neurones are activated by vol- nels. This block is typically use-dependent and the atile anaesthetics (Franks and Lieb, 1988; Winegar and depolarisation induced by the closing of leak K+ chan- Yost, 1998). This activation leads to membrane potential nels is expected to speed the generation of anaesthesia hyperpolarisation, suppressing action potential firing by first promoting Na+ channel opening. activity and neuronal transmission. Accordingly, the Volatile anaesthetics are known to have neuroprotec- cloned TREK1 and TREK2, but not TRAAK, channels, tive properties. Polyunsaturated fatty acids and lysophos- are opened by low concentrations of diethylether, pholipids also have protective roles and prevent neuronal , , and isofluorane, whereas TASK1 death in animal models of transient global ischemia and TASK3 channels are mainly activated by halothane (Lauritzen et al., 2000). These bioactive lipids are pro- and isofluorane (Fig. 2) (Patel et al., 1999; Lesage et al., duced from membrane phospholipids by phospholipase 2000). In rat somatic motoneurones, locus coeruleus and A2 during brain ischaemia. The release of these fatty raphe neurones, and cerebellar granule cells, volatile acids, in addition to cell swelling and intracellular aci- anaesthetics activate TASK-like acid-sensitive conduc- dosis, contribute to the opening of TREK channels. Acti- tances causing membrane potential hyperpolarisation and vation of these background conductances causes hyper- suppression of action potential discharge (Sirois et al., polarisation, reducing Ca2+ influx through voltage-gated 2000; Maingret et al., 2001; Washburn et al., 2002; Bay- Ca2+ channels and NMDA receptors, representing an liss et al., 2001). These effects on two-P-domain K+ important protective mechanism (Lauritzen et al., 2000). channels provide a molecular basis for clinical actions Interestingly, the neuroprotective agent riluzole (RP 6 F. Lesage / Neuropharmacology 44 (2003) 1–7

54274), which is used in the treatment of amyotrophic References lateral sclerosis, is also an activator of TREK channels. Activation of TREK1 and TREK2 by riluzole is transient Baker, M., Bostock, H., Grafe, P., Martius, P., 1987. Function and distribution of three types of rectifying channel in rat spinal root whereas TRAAK activation is sustained (Duprat et al., myelinated axons. Journal of Physiology (London) 383, 45–67. 2000). Riluzole has anti-ischemic, anticonvulsant, and Bayliss, D.A., Talley, E.M., Sirois, J.E., Lei, Q., 2001. TASK-1 is sedative properties that suggest that activation of TREK a highly modulated pH-sensitive ‘leak’ K+ channel expressed in currents could contribute to the neuroprotective action brainstem respiratory . Respiratory Physiology 129, 159– of this drug. Another neuroprotective drug, sipatrigine 174. Brickley, S.G., Revilla, V., Cull-Candy, S.G., Wisden, W., Farrant, (BW619C89), is a potent inhibitor of TREK1 and M., 2001. Adaptive regulation of neuronal excitability by a voltage- TRAAK. The related compound , which is a independent potassium conductance. Nature 409, 88–92. weaker neuroprotectant than sipatrigine, is also a less Buckler, K.J., Williams, B.A., Honore´, E., 2000. An oxygen-acid- and effective antagonist of these channels (Meadows et al., anaeshetic-sensitive TASK-like background in 2001). These reports appear contradictory to the neurop- rat arterial chemoreceptor cells. Journal of Physiology (London) 525, 135–142. rotection observed with polyunsaturated fatty acids, Chapman, C.G., Meadows, H.J., Godden, R.J., Campbell, D.A., Duck- lysophospholipids, anaesthetics, and riluzole, which are worth, M., Kelsell, R.E., Murdock, P.R., Randall, A.D., Rennie, known to open TREK channels. However, it can be pro- G.I., Gloger, I.S., 2000. Cloning, localisation and functional posed that in particular circumstances, the blocking of expression of a novel human, cerebellum specific, two pore domain leak K+ conductances might lead to depolarisation and potassium channel. Molecular Brain Research 82, 74–83. 2+ Czirjak, G., Enyedi, P., 2002. Formation of functional heterodimers subsequently to Ca channel inactivation, resulting in a between the TASK-1 and TASK-3 two-pore domain potassium 2+ decrease of Ca influx. channel subunits. Journal of Biological Chemistry 277, 5426–5432. The CNS stimulant ecstasy (3,4-methylenedioxyme- Doyle, D.A., Morais Cabral, J., Pfuetzner, R.A., Kuo, A., Gulbis, J.M., thamphetamine, MDMA) inhibits a background K+ con- Cohen, S.L., Chait, B.T., MacKinnon, R., 1998. The structure of + ductance in cultured rat hippocampal neurones and the potassium channel: molecular basis of K conduction and selec- tivity. 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