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 receptor, glycine receptor, cGMP-gated channel There are many diseases related to ion channels. Mutations in muscle voltage-gated sodium, potassium, calcium and chloride channels, and acetylcholine-gated channel may lead to such physiological disorders as hyper- and hypokalemic periodic paraly- sis, myotonias, long QT syndrome, Brugada syndrome, malignant hyperthermia and myasthenia. Neuronal disorders, e.g., epilepsy, episodic ataxia, 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 cystic fibrosis, 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 cell 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 Lipid Bilayer 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, hormone 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 ion channel disorder depolarisation of the cell membrane. 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- action potential. The process continues until peptide chains that are not processed cor- the resting potential 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- sodium channel (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. Paramyotonia congenita 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, myotonia congenita, 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 heart uSer804Phe, Val1293Ile, Met1360Val, rhythm (arrhythmia) 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