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Home , Potassium channel

Vol. 47 No. 3/2000

685–703

QUARTERLY

Review

Ion channels-related diseases*.

Beata Dworakowska½ and Krzysztof Do³owy½

Department of Biophysics, Agricultural University SGGW, Rakowiecka 26/30, 02-528 Warszawa, Poland Received: 20 July, 2000; accepted: 27 July, 2000

Key words: ion channels, channel-related genetic disorders, voltage-gated channels, nicotinic acetylcholine , glycine receptor, cGMP-gated channel

There are many diseases related to ion channels. Mutations in muscle voltage-gated , , and chloride channels, and acetylcholine-gated channel may lead to such physiological disorders as hyper- and hypokalemic periodic paraly- sis, myotonias, long QT syndrome, , and myasthenia. Neuronal disorders, e.g., epilepsy, , familial hemiplegic migraine, Lambert-Eaton myasthenic syndrome, Alzheimer’s disease, Parkinson’s disease, schizophrenia, hyperekplexia may result from dysfunction of voltage-gated sodium, potassium and calcium channels, or acetylcholine- and glycine-gated chan- nels. Some kidney disorders, e.g., Bartter’s syndrome, policystic kidney disease and Dent’s disease, secretion disorders, e.g., hyperinsulinemic hypoglycemia of infancy and , vision disorders, e.g., congenital stationary night blindness and to- tal colour-blindness may also be linked to mutations in ion channels.

There are many diseases related to proteins main types of channel gating. Voltage-gated embedded in membranes. Ion channels channels are opened by a change in mem- are one class of such molecules. Channel pro- brane potential. Molecules that bind to a spe- tein forms pores in cell membranes and allow cific site of the channel activate ligand-gated particular ions to pass through them down the channels. The third group comprises channels concentration gradient. A characteristic fea- activated by mechanical stimuli. Ion channels ture of ion channels is a gating mechanism are essential to a wide range of physiological that controls ion movement. There are three functions including neuronal signalling, mus-

*75th Anniversary of Membrane Concept. .Authors’ work was financed with grant No. 50406020011 from SGGW ½Beata Dworakowska/Krzysztof Do³owy: Tel./Fax (48 22) 849 1676; e-mail: [email protected]. waw.pl; [email protected] 686 B. Dworakowska and K. Do³owy 2000 cle contraction, cardiac pacemaking, but not identical domains. There are 6 trans- secretion, cell volume regulation and cell pro- membrane segments in each domain. The b liferation. It is not surprising that ion chan- subunit is a smaller polypeptide, with a single nels are implicated in numerous diseases. transmembrane segment and a large extra- Most of them are inherited disorders which re- cellular domain. The b subunit plays a role in sult from mutations in genes encoding chan- the gating of the channel, hastening the rates nel proteins. Some are autoimmune diseases at which it opens and closes. The voltage- in which the body produces antibodies to its gated channels of nerves and muscles are cru- own channel molecules. cial to nervous impulse propagation and mus- In 1989 the first disorder, cystic fibrosis, cle contraction. The channels are activated by was identified as an disorder depolarisation of the . In the (Tsui, 1992). From this moment the list of dis- open state they are selectively permeable to eases is still growing. The study of ion chan- sodium ions. The flow of ions into the cell pro- nels diseases usually consists of two stages. duces strong local depolarisation called action First, the chromosome locus of the disease potential that moves along the axon as new and the protein coded by that gene must be voltage-gated sodium channels opens due to identified. Then the function of mutant chan- the depolarisation. Potassium ion efflux nel expressed in special cells as HEK (human through depolarisation-activated voltage- embryonic kidney cells) or Xenopus oocytes is gated potassium channels and inactivation of studied with electrophysiological techniques. the voltage-gated sodium channels curtails the Gene mutations produce defective poly- . The process continues until peptide chains that are not processed cor- the is reset. Activation of rectly and are not incorporated into the mem- muscle voltage-gated sodium channels trig- brane or polypeptide chains that form chan- gers the flow of calcium ions into the cyto- nels but non-functional or with altered kinet- plasm from the sarcoplasmic reticulum and ics. Properties of channels may be studied by myofibril contraction. electrophysiological techniques. Whole-cell voltage clamp technique measures all chan- Muscle disorders nels of the cell in the same time. One can esti- mate maximum current flowing and its kinet- Mutations in the a subunit of voltage-gated ics. The patch clamp technique is able to mea- (SCN4A) causes two types of sure a single channel. Since the single channel autosomal dominant skeletal muscle disor- fluctuates between an open and a closed state ders: periodic paralysis and myotonia. one can determine current amplitude, open Hyperkalemic periodic paralysis is character- channel probability or the duration of the ised by attacks of muscle weakness or paraly- closed and the open state. sis between periods of normal muscle func- This article describes several ion channel tion. Attacks usually begin early in life. They types that are postulated to cause a diversity tend to occur while resting after exercise and of diseases, though detailed mechanisms of last 1–2 h. Weakness most commonly affects their contribution to observed symptoms is the muscles of the arms and legs. The level of still unclear. potassium in the blood is normal or high. Myotonia is a general name for the clinical symptom of delayed relaxation of skeletal VOLTAGE-GATED SODIUM CHANNELS muscle following voluntary contraction. The symptoms may worsen after repeated exer- Voltage-gated sodium channel is formed by cise. is characterised the a subunit chain, which has 4 homologous, by intermittent muscle stiffness or involun- Vol. 47 Ion channels-related diseases 687 tary contraction that is often triggered by Green et al., 1998; Bendahhou et al., 1999a; cold. Weakness may occur. Potassium-aggra- 1999b; Mitrovic et al., 1999; Rojas et al., 1999; vated myotonia is muscle stiffness triggered Takahashi & Cannon, 1999). Thr704Met and by potassium-rich food such as bananas. It in- Met1592Val are the most common mutations cludes three syndromes: myotonia fluctuans, in hyperkalemic periodic paralysis and a mild myotonia exacerbated by potassium Arg1448His, Arg1448Cys, Arg1448Pro in that varies in severity from day to day, paramyotonia congenita. myotonia permanens, a severe continuous Single channel recordings revealed that the myotonia, and acetazolamide-responsive mutations Met1360Val and Arg1448Cys, , a painful muscle stiff- Arg1448Pro increase the frequency of chan- ness. nel reopening and prolong mean open times More than 20 point mutations causing these (Wagner et al., 1997; Mitrovic et al., 1999). disorders have been described. Generally, the These reports indicate that the affected mutant channels exhibit abnormal, long-last- amino-acid residues are important for sodium ing currents that prolong membrane depolari- channel inactivation. The lack of full inactiva- sation. The effects of mutations in channels tion and strong depolarisation cause a portion expressed in HEK cells or Xenopus oocytes in- of sodium channels to enter a desensitised dicate that the slower decay of sodium current state leading to membrane inexcitability. This results from specific alterations of channel explains muscle weakness. Mild depolarisa- function as compared to the wild types: tion leads to increased membrane excitability uVal445Met, Thr704Met, Val1293Ile, and repeated activation of the contractile ap- Gly1306Glu, Ile1495Phe, Met1592Val: shift paratus that results in muscle stiffness. Some of steady-state activation to more negative mutations presumably make channels sensi- potentials, tive to temperature, producing symptoms ag- uSer804Phe, Gly1306Glu, Gly1306Val: shift gravated by cold (Featherstone et al., 1998). of steady-state fast inactivation to more pos- The site of substitution, size and charge of the itive potentials, new amino acid is important for the kind and uSer804Phe, Gly1306Glu, Gly1306Val, severity of symptoms. Thr1313Met, Arg1448Ser, Arg1448Cys, Arg1448Pro: slower rate of fast inactiva- Cardiac disorders tion, uVal445Met, Ile1495Phe: negative shift of Long QT syndrome is an autosomal domi- steady-state slow inactivation, nant (Romano-Ward syndrome) or a recessive uThr704Met, Met1592Val: impaired slow in- (Jervell and Lange-Nielsen syndrome) cardiac activation, disorder characterised by a very fast uSer804Phe, Val1293Ile, Met1360Val, rhythm () called “torsade de Arg1441Pro, Arg1441Cys, (Arg1441 is rat pointes” which leads to sudden loss of con- equivalent of human Arg1448), sciousness (syncope) and may cause sudden Arg1448Ser: more rapid recovery from the cardiac death, predominantly in young peo- fast inactivation state, ple. The QT interval on the electrocardiogram uThr704Met: faster recovery from the slow is the time from the onset of ventricular de- inactivation state, polarisation (the Q wave) to the completion of uThr704Met, Gly1306Glu, Gly1306Val, repolarisation (the end of the T wave). Long Gly1306Ala, Arg1441Pro, Arg1441Cys, QT is associated with two ion Arg1448Ser: slower deactivation channels: voltage-gated potassium channel (Mitrovic et al., 1995; Richmond et al., 1997; and voltage-gated sodium channel. The al- Wagner et al., 1997; Featherstone et al., 1998; tered ion channels function produces a pro- 688 B. Dworakowska and K. Do³owy 2000 longation of the ventricular action potential. 1999; Rook et al., 1999). This can increase in- Mutations in the a subunit of voltage-gated so- ward sodium current during the action poten- dium channel SCN5A causes the channel to tial upstroke. inactivate incompletely. Voltage-clamp stud- ies revealed that: Epilepsy uLys1505, Pro1506, Gln1507 deletions, Arg1623Gln and Glu1784Lys: channels Epilepsy is characterised by bursts of syn- show a sustained inward current during chronised discharges that cause seizures. membrane depolarisation, Generalised epilepsy with febrile seizures is uAsp1795 insertion: shift of steady-state ac- epilepsy provoked by the acute febrile illness. tivation of the channel to more positive po- It affects nerve cells of the whole brain. Fe- tentials, brile seizures afflict approximately 3% of all uAsp1790Gly and Asp1795 insertion: chan- children under six years of age and are by far nels shift steady-state inactivation to more the most common seizure disorder. A small negative potentials, proportion of children with febrile seizures uArg1623Gln: channel has significantly later develop ongoing epilepsy with afebrile slower macroscopic inactivation, seizures. It is an autosomal dominant disor- (An et al., 1998; Bennet et al., 1995; der. There are two candidates for the disor- Kambouris et al., 1998; Makita et al., 1998; der: a gene encoding the b1 subunit of volt- Bezzina et al., 1999; Wei et al., 1999). age-gated sodium channel (SCN1B) and a Single-channel recordings showed that the gene encoding the a subunit of voltage-gated Arg1623Gln mutant channel has prolonged sodium channel (SCN1A). Single amino-acid open times with bursting behaviour and in- changes in both chains were found (Wallace et creased probability of long openings al., 1998; Escayg et al., 2000b). Co-expression (Kambouris et al., 1998; Makita et al., 1998). of the Cys121Trp mutant b1 subunit with the In effect the mutant channels reopen during brain sodium channel a subunit in Xenopus prolonged depolarisation contributing to the laevis oocytes demonstrated that the mutation persistent inward current carried by sodium interferes with the ability of the subunit to ions that delays repolarisation. This produces modulate channel-gating kinetics. prolonged action potential. The Brugada syndrome (idiopathic ventricu- Malignant hyperthermia lar fibrillation) is abnormal heart function that is represented in the electrocardiogra- Malignant hyperthermia is an inherited con- phic pattern by right bundle branch block and dition that causes severe uncontrollable fever ST elevation in the right precordial leads during anaesthesia or while using muscle re- (early repolarisation). This autosomal domi- laxants. It is inherited as an autosomal domi- nant disorder may cause sudden death of nant trait. The anaesthetised patient rapidly young people. Mutations in the SCN5A car- develops high fever and muscle rigidity. Dur- diac voltage-gated sodium channel can be re- ing these episodes, muscle tissue is destroyed sponsible for the syndrome. Arg1512Trp, and released muscle pigments (myoglobin) Thr1620Met and Ala1924Thr mutant chan- may damage the kidneys and cause acute re- nels expressed in Xenopus oocytes or a mam- nal failure. Malignant hyperthermia can be fa- malian cell line resulted in faster current de- tal if not treated immediately. There was one cay than in wild-type channels, prolonged re- family reported by Moslehi et al. (1998) that covery from inactivation and shift of appeared to support the suggestion that a steady-state activation and inactivation to form of malignant hyperthermia is caused by more negative potentials (Dumaine et al., mutations in the SCN4A gene. Ryanodine re- Vol. 47 Ion channels-related diseases 689 ceptor and voltage-dependent calcium chan- Weerden (1990) concluded that the myokymic nel are more involved in malignant hyper- activity results from multiple impulse genera- thermia. tion in peripheral nerves. A number of differ- ent heterozygous missense point mutations of the neural voltage-gated potassium channel a VOLTAGE-GATED AND INWARDLY subunit (KCNA1/Kv1.1) have been identified. RECTIFYING POTASSIUM CHANNELS D’Adamo et al. (1999) and Adelman et al. (1995) studied the function of the Val408Cys Voltage-gated potassium channel is built mutant channel. They demonstrated that from 4 a protein chains surrounding a central Kv1.1 bearing this mutation produces chan- pore. Each subunit forms 6 transmembrane nels with threefold reduction of the mean regions. The b chain is a regulatory subunit open duration compared with the wild type, that can co-assemble with the a subunit to faster kinetics and increased inactivation. modulate the gating kinetics and enhance the The Phe184Cys mutation shifts the volt- stability of the multimeric complex. b is a age-dependence to more positive potentials. small polypeptide forming one transmem- The results suggest that affected nerve cells brane domain. The channels are important for cannot repolarise efficiently. It lowers the proper repolarisation after action potential. amount of excitation needed to produce ac- They are activated by depolarisation after so- tion potentials. This leads to uncontrolled dium channels activation. The flow of potas- muscle contractions. sium ions out of the cell contributes to the re-establishing of resting potential. Long QT syndrome and congenital hearing Another class of potassium channels is in- loss ward rectifiers. The channel is made from 4 identical subunits. They have 2 membrane- Long QT, as described in the previous chap- spanning segments and 1 pore-lining seg- ter, is a disorder of cardiac repolarisation. ment. HERG is atypical with 6 transmem- Mutations in 4 cardiac voltage-gated potas- brane segments. Inward rectifiers open at sium channels are associated with long QT membrane potentials near to or more nega- syndrome: KCNA8 (KCNQ1, KVLQT1) tive than the resting potential and allow potas- thought to be the one most commonly respon- sium ions to flow inwards but not outwards. sible, KCNE1, KCNE2 (minK) and KCNH In the heart, these channels also have small (HERG). KCNQ1 encodes the a subunit of po- outward conductance that regulate resting po- tassium channel. There are about 30 muta- tential and contribute to the terminal phase of tions in the KCNQ1 gene that could cause ei- repolarisation. At positive voltages, these ther Romano-Ward syndrome or Jervell and channels close and thus help maintain the Lange-Nielsen syndrome. The mutations have level of resting potential. two different effects: failing to produce func- tional channels (Arg174Cys, Glu261Lys) or al- tering channel kinetics. The mutations that Episodic ataxia with myokymia syndrome produce functional channels: Episodic ataxia with myokymia syndrome is ureduce macroscopic conductance a dominantly inherited disorder. It is charac- (Leu272Phe, Ala300Thr), terised by brief episodes of incoordination ushift the voltage-dependence of activation (ataxia) with continuous muscle movement strongly to more positive potential (myokymia) at other times. Abrupt postural (Arg243His, Trp258Arg, Arg533Trp, change, emotion and vestibular stimulation Arg539Trp, Arg555Cys), provoke it. Attacks last minutes. Brunt & van 690 B. Dworakowska and K. Do³owy 2000

uslow the rate of activation (Arg243Cys, (Ile593Arg, Tyr611His, Gly628Ser, Trp248Arg), Val822Met) do not functionally express (Zhou uaccelerate deactivation (Arg243His, et al., 1998) or alter channel kinetics: Trp248Arg, Arg555Cys) uThr474Ile, Asn470Asp, Arg534Cys acti- (Chouabe et al., 1997; Shalaby et al., 1997; Pri- vate at more negative voltages, ori et al., 1998; Franqueza et al., 1999; uArg534Cys accelerates activation, Chouabe et al., 2000; Schmitt et al., 2000). The uArg56Gln, Asn33Thr activate more slowly mutations generally diminish outward repo- and at more positive voltages, larising potassium current, which prolongs uPhe29Leu, Asn33Thr, Gly53Arg, . This can cause sud- Arg56Gln, Cys66Gly, His70Arg, den . Ala78Pro, Leu86Arg, Arg534Cys acceler- KCNE1 codes for the b subunit that ate deactivation, coassembles with the KCNQ1 a subunit to uAsn629Asp: channel is nonselective for form the slowly activating cardiac potassium monovalent cations and replaces the out- channel. The outward current of this channel ward repolarising current with the inward has an increased amplitude and reaches its depolarising sodium current steady state only after 50 s. The ab channels (Zhou et al., 1998; Chen et al., 1999a; make the contribution of potassium current to Nakajima et al., 1999; Lees-Miller et al., 2000). the cardiomyocyte repolarisation strongly de- The mutations are predicted to result in a di- pendent on the and on its regula- minished magnitude of potassium inwardly tory state. Co-expression of mutant KCNE1 rectifying current consistent with the pro- with KCNQ1 produces reduced currents longed LQ interval observed in affected indi- through channels with altered gating, lowered viduals. amplitudes (Val47Phe, Trp87Arg) and accel- KCNE1 can also assemble with HERG to erated deactivation (Ser74Leu, Asp76Asn) as modulate the rapid delayed rectifier current. compared with wild-type channels (Splawski Then mutations in KCNE1 may lead to the et al., 1997; Bianchi et al., 1999). syndrome. Such mutations are observed and HERG encodes an inwardly rectifying potas- effect in suppressed HERG current (Bianchi sium channel that mediates repolarisation of et al., 1999). ventricular action potentials. HERG channels KCNE2 is the gene encoding the MinK-re- show gating properties consistent with many lated peptide, a small integral membrane sub- of the inwardly rectifying potassium chan- unit that assembles with the HERG channel to nels, but they also have an inactivation mecha- alter its function. Three missense mutations nism that attenuates efflux during depolarisa- associated with long QT syndrome and ven- tion. The channels inactivate much more rap- tricular fibrillation (Gln9Glu, Met54Thr, idly than they activate. The result is that most Ile57Thr) were identified in the KCNE2 gene HERG channels are closed during the plateau (Abbott et al., 1999). Mutants form channels phase of cardiac action potential. Rapid recov- that open slowly and close rapidly, thereby di- ery from inactivation during repolarisation minishing potassium currents. combined with a very slow subsequent transi- Congenital hearing loss is associated with tion to the closed state (deactivation) result in Jervell and Lange-Nielsen syndrome and mu- increased inwardly rectifying potassium cur- tations in the KCNE1, KCNQ1 (Neyroud et al., rent during the terminal phase of cardiac re- 1997) and the KCNQ4 (Kubisch et al., 1999) polarisation. The increased incidence of car- gene of voltage-gated potassium channels. diac sudden death has been observed in pa- They are expressed in the inner ear. KCNQ1 is tients that lack HERG currents because they expressed as a complex with KCNE1 in the carry a genetic defect. Such mutants cells of a specialised endothelium, stria Vol. 47 Ion channels-related diseases 691 vascularis. The stria is responsible for secre- 10–16% risk of developing epilepsy again later tion of endolymph, the potassium-rich fluid in life. Two a subunits of brain voltage-gated that fills the middle chamber of the cochlea potassium channels are associated with the and bathes the sound-receptive hair cells. In disorder: KCNQ2 and KCNQ3. Mutations Jervell and Lange-Nielsen syndrome have been found in these subunits which are endolymph secretion does not occur normally, responsible for epileptic seizures. Expression the middle chamber of cochlea collapses, and of the mutant channel in Xenopus oocytes did hair cells degenerate. KCNQ4 is expressed in not yield measurable currents (Biervert et al., the outer hair cells. Their function is to in- 1998) or significantly reduced the potassium crease the sensitivity of sound perception by current (Lerche et al., 1999). The KCNQ2 and mechanically amplifying sound vibrations KCNQ3 channel subunits can coassemble to within the cochlea. Mutations abolish the po- form the M-channel. It opens occasionally at tassium current and probably exert an effect the resting potential and is slowly activated by on endolymph homeostasis. depolarisation. M-channel activation causes a delayed membrane hyperpolarisation after a cell receives an excitatory input. Dysfunction Bartter’s syndrome of M-Channels causes neurones to become Bartter’s syndrome is an autosomal reces- slightly depolarised and to fire multiple action sive form of often severe intravascular vol- potentials rhythmically after receiving excit- ume depletion due to renal salt-wasting associ- atory inputs. ated with alkalosis (a condition of excess base in body fluids) with reduced potassium Hyperinsulinemic hypoglycemia of infancy (hypokalemic alkalosis), hypercalciuria (the presence of excess calcium in the urine) and Hyperinsulinemic hypoglycemia of infancy increased production of the hormone (HHI) is an autosomal recessive disorder of aldosterone. Patients with Bartter’s syn- glucose metabolism characterised by unregu- drome are often critically ill from birth on- lated secretion of and profound hypo- wards leading to renal failure. Mutations in glycemia. Thomas et al. (1996) discovered a the KCNJ1 gene coding for inwardly rectify- Kir6.2 (inwardly rectifying potassium chan- ing potassium channel (Kir 1.1) leading to loss nel) gene mutation in an affected individual of function are associated with the disease. with severe HHI. The ATP-sensitive potas- Potassium channel in the kidney probably sium current of the affected channel plays a plays a major role in K+ homeostasis. Disor- role in secretion and muscle contraction by der of channel function disrupts potassium re- coupling metabolic activity to membrane po- cycling back to the tubule lumen and inhibits tential. In pancreatic beta cells, ATP-potas- thereby the sodium-potassium 2 chloride sium channels are crucial for the regulation of cotransporter activity (Karolyi et al., 1998). glucose-induced insulin secretion (Sharma et Classic Bartter’s syndrome results from de- al., 2000). fective chloride transport.

VOLTAGE-GATED CALCIUM Epilepsy CHANNELS Benign neonatal epilepsy is an autosomal dominant form of epilepsy characterised by Voltage-gated calcium channels consist of recurrent, brief, generalised seizures that be- the large principal subunit called a1, which gin on about the fourth day of life and cease af- contains the channel pore, together with regu- ter 1–3 months. Affected persons carry a latory a2, b, c and d subunit. The a1 subunit 692 B. Dworakowska and K. Do³owy 2000 has 4 homologous domains with 6 transmem- tions in the CACNA1A (CACNL1A4) gene, brane segments each. Calcium channels are which codes for the pore forming a1A subunit found in brain, muscle, and a wide variety of of voltage-gated (Ophoff et other tissues. They are entirely responsible al., 1996). The channels are present in the for voltage-gated depolarisation in vertebrate presynaptic terminal of motor axon. They are , and serve to maintain depola- involved in the control of membrane excitabil- risation during the plateau of action potential ity and release. The muta- in vertebrate heart muscle. They are also cru- tions probably produce non-functioning chan- cially important in controlling the internal cal- nels. cium ion concentration in many muscle cells, The Ca2+ channel b subunits regulate volt- secretory cells and at nerve terminals. Cal- age-dependent calcium currents through di- cium ions act also as intracellular messengers rect interaction with the a1 subunits. The b and calcium channels are intimately involved and a1-binding motifs are conserved, and all b in regulation of cell functions. subunits can stimulate current amplitude, voltage dependence, and kinetics. Inactiva- tion of the b4 subunit of calcium channel in Hypokalaemic periodic paralysis the lethargic mouse neurological mutant re- Hypokalaemic periodic paralysis is an sults in a complex neurological disorder that autosomal dominant skeletal muscle disorder includes ataxia. Escayg et al. (2000a) found a in which episodes of muscle weakness occur. premature termination mutation in members Affected people have first attacks of limb of an affected family. weakness as teenagers. Patients have low se- rum potassium levels. The disorder is associ- Familial hemiplegic migraine ated with mutations in the skeletal muscle voltage-gated calcium channel a1 subunit Familial hemiplegic migraine, a rare auto- (CACNA1S, CACNL1A3), especially in the somal dominant disorder, is characterised by voltage sensor regions of the channel. They attacks of hemicranial pain. There are reports lead to calcium currents with reduced ampli- that a dysfunction of the CACNL1A4 channel tude and voltage-dependence shifted to more a1A subunit may be involved (Ophoff et al., negative potentials (Arg528His) or to more 1996; Spranger et al., 1999). Expression ex- positive potentials (Arg1239His, Arg1239Gly) periments show that mutations in the calcium (Morrill & Cannon, 1999). Voltage-gated cal- channel alter inactivation gating and can lead cium channels in skeletal muscle are involved to both gain and loss of function of the chan- as voltage sensors in excitation-contraction nel (Kraus et al., 1998; Hans et al., 1999). coupling, a process whereby electrical signals generated by action potentials at the muscle Lambert-Eaton myasthenic syndrome cell surface are transduced into intracellular Lambert-Eaton myasthenic syndrome is an release of calcium and ultimately muscle fibre autoimmune disease, caused by antibodies to contraction. Rapid inactivation seems to in- calcium channels at the nerve terminal on terfere with this process and leads to the ob- which acetylcholine release depends. The tar- served symptoms. gets of antibodies are the a1 subunits of P/Q-type voltage-gated calcium channel Episodic ataxia (Takamori et al., 2000). This results in a de- crease in the amount of acetylcholine released As already mentioned, episodic ataxia is a by the nerve impulse. Patients typically have lack of coordination. It can result from muta- weakness of legs and arms. Vol. 47 Ion channels-related diseases 693

Epilepsy during excitation-contraction coupling. Muta- tions alter the channel kinetics for calcium in- To determine the role of the CACNB4 gene activation and make the channel hyper- and encoding the b4 subunit in this human disor- hyposensitive to activating and inactivating der, Escayg et al. (2000a) screened for muta- ligands, respectively. Calcium release chan- tions in small pedigrees with familial epilepsy nels open persistently, causing sustained and ataxia. A premature-termination muta- muscle contraction, fever and muscle injury. tion was identified in a patient with juvenile Mutations in other channels are less common myoclonic epilepsy (brief spells of loss of con- causes of malignant hyperthermia e.g., muta- sciousness and repetitive bilateral myoclonic tion in the a1 subunit of the human skeletal jerks in the shoulders and arms after awaken- muscle L-type voltage-dependent calcium ing, without loss of consciousness). It lacks channel (CACNL1A3) (Monnier et al., 1997). the 38 C-terminal amino acids containing part of an interaction domain for the a1 subunit. The missense mutation Cys104Phe was iden- VOLTAGE-GATED CHLORIDE tified in a German family with generalised epi- CHANNELS lepsy. The Ca2+ channel b subunit regulates voltage-dependent calcium currents through Voltage-gated chloride channels have several direct interaction with the a1 subunit. The re- functions including the regulation of cell vol- sults of functional tests of the truncated pro- ume, stabilisation, signal tein in Xenopus laevis oocytes demonstrated a transduction and transepithelial transport. small decrease in the fast time constant for They are located in all tissues. The model of the inactivation of the cotransfected a1 sub- the channel structure assumes 4 subunits, unit. Further studies will be required to evalu- each with 13 domains but not all of the seg- ate the in vivo consequences of these muta- ments actually cross the membrane. Muscle tions. chloride channels regulate the electric excit- ability of the skeletal muscle membrane by Congenital stationary night blindness holding membrane potential near its resting level. Kidney chloride channels are presum- Congenital stationary night blindness is a re- ably important for Cl– reabsorption. cessive, nonprogressive retinal disorder char- acterised by decreased visual acuity and loss of night vision. Mutation analysis of the Myotonia CACNA1F gene coding for the a1F subunit ex- Myotonia or muscle stiffness is a muscle ab- pressed in retina in 20 families with the syn- normality in which relaxation after voluntary drome revealed 6 different mutations, all of contraction is delayed. The stiffness lessens which predicted premature protein termina- as muscles are used. Myotonia is based on the tion (Bech-Hansen et al., 1998). hyperexcitability of the muscle fibre mem- brane. There are two types of the syndrome. Malignant hyperthermia The recessive form, in which the stiffness As it was already mentioned this is a disor- starts in childhood in the leg muscles and der provoked by general anaesthesia. Muta- spreads to the arms, neck and face, is known tions in the sarcoplasmic calcium release as Becker’s disease or generalised myotonia. channel (, RYR1) are the Less severe Thomsen’s disease or myotonia most frequent cause of malignant hyper- congenita is a dominant form. Myotonias are thermia (McCarthy et al., 2000). The channels associated with mutations in the muscle volt- mediate calcium release in skeletal muscle age-gated CLC-1. Mutations 694 B. Dworakowska and K. Do³owy 2000 seem to have different effects on channel mination, either abolish or markedly reduce function: chloride conductance (Lloyd et al., 1996; uVal165Gly, Phe167Leu, Gly200Arg, Igarashi et al., 1998). Gunther et al. (1998) Val236Leu, Gly285Glu, Val286Ala, and George (1998) showed that the CLCN5 Ile290Met, Phe307Ser, Ala313Thr, gene is expressed in renal proximal tubule Arg317Gln, Ile329Thr, Arg338Gln, cells, which normally endocytose proteins Phe413Cys, Pro480Leu, Gln552Arg, passing the glomerular filter. Gunther et al. Ile556Asn: shift of channel activation to- (1998) suggested that CLC-5 might be essen- ward positive voltages so the channel open tial for proximal tubular endocytosis by pro- probability is near 0 at resting potential, viding an electrical shunt necessary for the ef- uGly230Glu: changes in anion and cation ficient acidification of vesicles in the endo- selectivity and the cation-to-anion perme- cytotic pathway, explaining the proteinuria ability ratio; outward rectification instead observed in Dent’s disease. of the wild-type inward rectification at pos- Classic Bartter’s syndrome has been demon- itive potentials, strated to result from defective chloride trans- uMet485Val: reduction of single channel port across the basolateral membrane in the conductance distal due to mutations in the kidney (Pusch et al., 1995; Fahlke et al., 1997; chloride channel gene. Examination of this Wollnik et al., 1997; Kubisch et al., 1998; gene reveals loss-of-function mutations that Zhang et al., 2000). impair renal chloride reabsorption (Simon et The mutant channels cannot contribute sig- al., 1997). nificantly to the repolarisation of action po- tentials. Without such repolarisation, sodium channels have enough time to recover from in- NICOTINIC ACETYLCHOLINE activation leading to typical myotonic runs, RECEPTOR CHANNELS which are a series of repetitive action poten- tials. The nicotinic acetylcholine receptor (nAChR) channels are among the best known of channels. They consist of 5 subunits: two a Kidney disorders chains and one b, one c or one e and one d X-linked nephrolithiasis, or Dent’s disease, chain. The e subunit occurs in adult mam- encompasses several clinical syndromes of mals. It takes place of the c subunit present in low molecular weight proteinuria (the pres- newly born. The nAChR channels are present ence of excess protein in the urine), hyper- in the postsynaptic membrane of vertebrate calciuria (the presence of excess calcium in muscle and nervous cells. Electrical stimula- the urine), nephrocalcinosis (deposition of cal- tion of the presynaptic axon releases acetyl- cium oxalate or phosphate in renal tubules choline into the synaptic gap. Acetylcholine and the areas between the tubules), combines with nAChRs. Their channels open nephrolithiasis (kidney stones), and renal fail- and allow sodium and potassium ions to flow ure. It is associated with mutations in the through. The resulting depolarisation acts as CLCN5 gene encoding the kidney-specific volt- a trigger for the activation of voltage-gated age-gated outwardly rectifying chloride chan- channels and ultimately for muscle contrac- nel (CLC-5). Expression in Xenopus oocytes of tion or propagation of the nerve impulse along wild type and the mutants demonstrated that the neurone. Neuronal nAChRs are also found the mutations, Leu200Arg, Ser270Arg, in presynaptic membranes. They are impli- Leu278Phe, Trp279termination, Gly506Glu, cated in controlling and modulating the re- Ser520Pro, Arg648termination, Arg704ter- lease of various . Vol. 47 Ion channels-related diseases 695

Congenital myasthenia residue, which participates in agonist bind- ing. The mutation reduces the affinity of Disorders of the neuromuscular junction nAChR for ACh and the rate of channel open- lead to several types of myasthenia. Slow ing. Fewer receptors are activated, and those, channel congenital myasthenia is an inherited which are, exhibit shorter burst duration. The autosomal dominant syndrome, characterised excitatory postsynaptic current is reduced by muscle weakness, rapid fatigue, progres- and depolarisation is too small to elicit the ac- sive muscle atrophy, generation of repetitive tion potential. muscle action potentials in response to a sin- gle nerve stimulus, and degeneration of the postsynaptic region of the muscle. It results Myasthenia gravis from mutations in the muscle nAChR chan- Myasthenia gravis is an autoimmune disease nel. There are many identified mutations in caused by antibodies directed toward nAChR. all adult subunits: It consists in muscle weakness that usually in- uaGly153Ser, aVal249Phe, bVal266Met, creases with continued activity but improves eThr264Pro, eLeu269Phe increase the re- after periods of rest. Any muscle can be af- ceptor’s affinity for ACh, fected, however, the muscles that control eye uaGly153Ser, aAsn217Lys, aVal249Phe al- movement, the eyelids, facial expression and low multiple reopenings before ACh dissoci- swallowing are most frequently affected. The ation, disease results from a reduction in the num- uaAsn217Lys, bVal266Met, eThr264Pro, ber of functional nAChR by lysis of the eLeu269Phe slow the rate of channel clos- postsynaptic membrane following antibody ing, binding, which leads to destruction of the uaVal249Phe, bVal266Met, eThr264Pro, endplate region of the muscle (Engel et al., eLeu269Phe increase spontaneous opening 1977). Blocking of the receptor by antibodies of the channel, which reduces peak current amplitude has uaAsn217Lys, aVal249Phe, eLeu269Phe en- also been demonstrated (Bufler et al.,1998). hance desensitisation (Ohno et al., 1995; Sine et al., 1995; Engel et al., 1996; Gomez et al., 1997; Milone et al., Epilepsy 1997). The increased duration of channel opening Autosomal dominant nocturnal frontal lobe or bursts of openings produce a prolonged ex- epilepsy is a rare form of partial epilepsy that citatory postsynaptic current, prolonged de- causes brief, frequent and violent seizures al- polarisation of the muscle membrane, inacti- most exclusively during light sleep. A single vation of voltage-gated Na+ channels and fail- mutation in the neuronal nAChR a4 subunit ure of muscle excitability. The prolonged de- was detected in affected individuals: phenyl- polarisation also causes enhanced Ca2+ entry, alanine replaced serine as the 247th residue, a which may account for the progressive de- highly conserved amino acid in the second struction of the postsynaptic neuromuscular transmembrane domain (Steinlein et al., junction. 1995). It is thought to lie within the pore as it Fast channel syndrome resembles symp- is in the binding site for , toms of slow channel syndrome, but mutation which is an open . Expression in the nAChR channel produces a reduction in of the mutant channel in Xenopus oocytes re- ACh affinity and decreases the rate of channel sulted in faster desensitisation to ACh and openings. Ohno et al. (1996) reported a muta- slower recovery from desensitisation than tion, ePro121Leu that causes fast channel that of the wild type channel (Weiland et al., syndrome. It lies in the e subunit close to the 1996; Kuryatov et al., 1997). The effect of the 696 B. Dworakowska and K. Do³owy 2000 mutation is to decrease the channel open tion of inhibitory interneurones manifested time, reduce single channel conductance and as decreased gating of response to sensory increase the rate of desensitisation. The possi- stimulation. ble connection of these activity changes with epilepsy is that a4-containing nAChRs might mediate the release of the inhibitory neuro- GLYCINE RECEPTOR transmitter GABA. The reduction in nAChR function would then result in the enhanced ex- Glycine receptor is a neurotransmitter-gated citability of postsynaptic neurones and lower ion channel. Binding of glycine to its receptor the seizure threshold. increases the chloride conductance and thus produces hyperpolarisation that inhibits Other human central nervous system disor- neuronal firing. The channel is a pentamer ders composed of a and b subunits. The subunit has 4 transmembrane domains. Alzheimer’s disease (AD), Parkinson’s dis- ease (PD) and schizophrenia can be also asso- ciated with the neuronal nAChR, though the Hyperekplexia mechanism is still unknown. AD and PD are neurological degenerative disorders. AD is Hyperekplexia (or startle disease) is an characterised by loss of memory and difficulty autosomal dominant neurologic disorder in learning. Eventually all mental functions characterised by muscular rigidity of central fail. Microscopic examination shows that nervous system origin, particularly in the neo- cholinergic cells of the brain producing acetyl- natal period, and by an exaggerated startle re- choline die and disappear. PD symptoms are sponse to unexpected acoustic or tactile stim- tremor or trembling of hands, arms, legs, jaw uli. It results from mutations in the a1 sub- and face, rigidity of the limbs and trunk, slow- unit of glycine receptor chloride channels that ness of movement. The hallmark of the dis- disrupt inhibitory synaptic transition. The ease is the loss of brain cells producing dopa- most frequently observed mutation is mine. There is general consensus that the Arg271Leu or Arg271Gln. These and other number of cortical neuronal nicotinic recep- mutations: Pro250Thr, Gln266His and tors is decreased in both diseases. It is con- Lys276Glu, lead to reduced chloride current firmed in recent studies (Rinne et al., 1991; due to abnormal channel kinetics: lower sensi- Perry et al., 1995). Loss of the nicotinic recep- tivity to glycine, and reduced open times. tor may precede degeneration of cholinergic Arg271Leu, Arg271Gln decreased single and dopaminergic neurones in affected re- channel conductance (Rajendra et al., 1994; gions. Lewis et al., 1998; Moorhouse et al., 1999; The possible involvement of nicotinic recep- Saul et al., 1999). tors in schizophrenia has been suggested by the high prevalence of smoking in schizo- phrenic patients. A cluster of symptoms that CYSTIC FIBROSIS CHLORIDE typically include delusions, hallucinations, CHANNELS disordered thinking, and emotional unrespon- siveness describes the disease. Preliminary Cystic fibrosis transmembrane conductance experiments indicate that patients have fewer regulator (CFTR) has 2 membrane-spanning ligand binding sites in the hippocampus domains, each with 6 putative transmem- (Freedman et al., 1995; Leonard et al., 1996). brane segments. It is activated by cAMP. The It might lead to a failure of cholinergic activa- channel is localised to the apical membranes Vol. 47 Ion channels-related diseases 697 of epithelial cells lining air tracts and secre- in vertebrate photoreceptor cells. These chan- tory tubules. nels are responsible for the flow of sodium and calcium ions into the rod outer segments in the dark. This depolarises the cell mem- Cystic fibrosis brane. Light absorption by the visual pigment Cystic fibrosis is a hereditary disease that af- leads indirectly to the activation of cGMP flicts about one in 2500 children. Sufferers phosphodiesterase which breaks down cGMP have thick mucous secretion that blocks the and so closes the channels. The retinal rod smaller lung airways and the ducts of pan- cGMP-gated cation channel is a hetero-oli- creas. This leads to inflammation and infec- gomer composed of 2 homologous subunits, a tion of the lung and , then progres- and b, each with cytoplasmic N and C termini sive destruction of both organs and eventual and 6 putative transmembrane domains. death, usually before 30. There is also exces- sive salt loss in the sweat glands. Cystic fibro- Total colour-blindness sis results from a failure of chloride transport that is associated with mutations of the gene Total colour-blindness, also referred to as coding for the CFTR channel. Normally water rod monochromacy (RM) or complete movement follows chloride efflux through the achromatopsia, is a rare, autosomal recessive channels into the lumen of the tubules. Fail- congenial disorder characterised by ure of chloride transport results in a reduc- photophobia, reduced visual acuity, nystag- tion in the amount of fluid produced by epithe- mus and a complete inability to discriminate lial cells, so they become blocked with thick se- between colours. Kohl et al. (1998) reported cretions. About 500 mutations have been the identification of missense mutations in identified in the CFTR gene. The most com- CNGA3 (a3 subunit) in 5 families with RM. mon and severe mutation (occurs in 70% of all defective CFTR genes) is the deletion of phenylalanine at position 508. This mutation leads to the retention of channel protein NONSELECTIVE CATION CHANNELS within the cell and failure of channel traffick- ing to the plasma membrane (Cheng et al., Polycystic kidney disease 1990). Many other mutations have the same effect (Vankeerberghen et al., 1998). Milder Polycystic kidney disease (PKD) comes in forms of the disease result from such muta- two hereditary forms: the autosomal domi- tions as Arg117His, Glu193Lys, Arg334Trp nant form is one of the most common life- and Arg347Pro which produce channels that threatening genetic diseases. In the syn- are less likely to open or have reduced ampli- drome, cysts develop in both kidneys. The tude (Sheppard et al., 1993; Seibert et al., cysts may range in size from a pinhead to the 1997). size of a grapefruit. When many cysts de- velop, the kidneys can grow to a football size or larger. The first documented case of PKD cGMP-GATED CATION CHANNELS dates back to Stefan Batory, the King of Po- land. There are reports that the gene mutated Cyclic nucleotide-gated (CNG) cation chan- in most cases of the disease codes for pore nels are essential in visual and olfactory sig- forming subunits of a channel permeable to nal transduction. Cyclic guanosine monophos- sodium, potassium and calcium ions (Nomura phate (cGMP) opens cation-selective channels et al., 1998; Chen et al., 1999). 698 B. Dworakowska and K. Do³owy 2000

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