The past few years have seen the elucidation of several neurological diseases caused by inherited mutations of ion channels. In contrast to many other types of genetic disorders, the “channelopathies” can be studied with high precision by applying electrophysiological methods. This review evaluates the success of this approach in explaining the mechanisms of two forms of episodic ataxia that are known to be caused by mutations of ion channels: episodic ataxia type 1 (EA1, caused by K+ channel mutations) and episodic ataxia type 2 (EA2, caused by Ca2+ channel mutations). Although both of these disorders are rare, they raise many important questions about the roles of identified channels in brain function. Indeed, a resolution of the mechanisms by which both diseases occur will represent a major milestone in understanding diseases of the CNS, in addition to opening the way to novel possible treatments.
Adelman JP, Bond CT, Pessia M, Maylie J. 1995. Episodic ataxia results from voltage-dependent potassium channels with altered functions. Neuron15:1449-1454.
2.
Ashcroft FM. 2000. Ion channels and disease. San Diego: Academic Press.
3.
Bain PG, O’Brien MD, Keevil SF, Porter DA. 1992. Familial periodic cerebellar ataxia: a problem of cerebellar intracellular pH homeostasis. Ann Neurol31:147-154.
4.
Baloh RW, Yue Q, Furman JM, Nelson SF. 1997. Familial episodic ataxia: clinical heterogeneity in four families linked to chromosome 19p. Ann Neurol41:8-16.
5.
Battistini S, Stenirri S, Piatti M, Gelfi C, Righetti PG, Rocchi R, and others. 1999. A new CACNA1A gene mutation in acetazolamide-responsive familial hemiplegic migraine and ataxia. Neurology53:38-43.
6.
Boland LM, Price DL, Jackson KA. 1999. Episodic ataxia/myokymia mutations functionally expressed in the Shaker potassium channel. Neuroscience91:1557-1564.
7.
Bourinet E, Soong TW, Sutton K, Slaymaker S, Mathews E, Monteil A, and others. 1999. Splicing of alpha 1A subunit gene generates phenotypic variants of P- and Q-type calcium channels. Nat Neurosci2:407-415.
8.
Bretschneider F, Wrisch A, Lehmann-Horn F, Grissmer S. 1999. Expression in mammalian cells and electrophysiological characterization of two mutant Kv1.1 channels causing episodic ataxia type 1 (EA-1). Eur J Neurosci11:2403-2412.
9.
Browne DL, Gancher ST, Nutt JG, Brunt ER, Smith EA, Kramer P, and others. 1994. Episodic ataxia/myokymia syndrome is associated with point mutations in the human potassium channel gene, KCNA1. Nat Genet8:136-140.
10.
Campbell DB, Hess EJ. 1999. L-type calcium channels contribute to the tottering mouse dystonic episodes. Mol Pharmacol55:23-31.
11.
Coleman SK, Newcombe J, Pryke J, Dolly JO. 1999. Subunit composition of Kv1 channels in human CNS. J Neurochem73:849-858.
12.
Comu S, Giuliani M, Narayanan V. 1996. Episodic ataxia and myokymia syndrome: a new mutation of potassium channel gene, KCNA1. Ann Neurol40:684-687.
13.
D’Adamo MC, Imbrici P, Sponcichetti F, Pessia M. 1999. Mutations in the KCNA1 gene associated with episodic ataxia type-1 syndrome impair heteromeric voltage-gated K(+) channel function. FASEB J13:1335-1345.
14.
D’Adamo MC, Liu Z, Adelman JP, Maylie J, Pessia M. 1998. Episodic ataxia type-1 mutations in the hKv1.1 cytoplasmic pore region alter the gating properties of the channel. Embo J17:1200-1207.
15.
de Leon M, Wang Y, Jones L, Perez-Reyes E, Wei X, Soong TW, and others. 1995. Essential Ca(2+) binding motif for Ca(2+) sensitive inactivation of L-type Ca(2+) channels. Science270:1502-1506.
16.
Denier C, Ducros A, Vahedi K, Joutel A, Thierry P, Ritz A, and others. 1999. High prevalence of CACNA1A truncations and broader clinical spectrum in episodic ataxia type 2. Neurology52:1816-1821.
17.
Dove LS, Abbott LC, Griffith WH. 1998. Whole-cell and single-channel analysis of P-type calcium currents in cerebellar Purkinje cells of leaner mutant mice. J Neurosci18:7687-7699.
18.
Escayg A, De Waard M, Lee DD, Bichet D, Wolf P, Mayer T, and others. 2000. Coding and noncoding variation of the human calcium-channel beta4-subunit gene CACNB4 in patients with idiopathic generalized epilepsy and episodic ataxia. Am J Hum Genet66:1531-1539.
19.
Eunson L, Rea R, Zuberi SM, Youroukos S, Panayiotopoulos CP, Liguori R, and others. 2000. Clinical, genetic and expression studies of mutations in the potassium channel gene KCNA1 reveal new phenotypic variability. Ann Neurol48:647-656.
20.
Fletcher CF, Frankel WN. 1999. Ataxic mouse mutants and molecular mechanisms of absence epilepsy. Hum Mol Genet8:1907-1912.
Griggs RC, Moxley RTd, Lafrance RA, McQuillen J. 1978. Hereditary paroxysmal ataxia: response to acetazolamide. Neurology28:1259-1264.
23.
Hanna MG, Wood NW, Kullmann DM. 1998. Ion channels and neurological disease: DNA based diagnosis is now possible, and ion channels may be important in common paroxysmal disorders. J Neurol Neurosurg Psychiatry65:427-431.
24.
Hans M, Luvisetto S, Williams ME, Spagnolo M, Urrutia A, Tottene A, and others. 1999. Functional consequences of mutations in the human alpha 1A calcium channel subunit linked to familial hemiplegic migraine. J Neurosci19:1610-1619.
25.
Hess EJ, Wilson MC. 1991. Tottering and leaner mutations perturb transient developmental expression of tyrosine hydroxylase in embryologically distinct Purkinje cells. Neuron6:123-132.
26.
Jen J. 1999. Calcium channelopathies in the central nervous system. Curr Opin Neurobiol9:274-280.
27.
Jen J, Yue Q, Nelson SF, Yu H, Litt M, Nutt J, and others. 1999. A novel nonsense mutation in CACNA1A causes episodic ataxia and hemiplegia. Neurology53:34-37.
28.
Jodice C, Mantuano E, Veneziano L, Trettel F, Sabbadini G, Calandriello L, and others. 1997. Episodic ataxia type 2 (EA2) and spinocerebellar ataxia type 6 (SCA6) due to CAG repeat expansion in the CACNA1A gene on chromosome 19p. Hum Mol Gen6:1973-1978.
29.
Jun K, Piedras-Renteria ES, Smith SM, Wheeler DB, Lee SB, Lee TG, and others. 1999. Ablation of P/Q-type Ca(2+) channel currents, altered synaptic transmission, and progressive ataxia in mice lacking the alpha (1A)-subunit. Proc Natl Acad Sci USA96:15245-15250.
Kraus RL, Sinnegger MJ, Koschak A, Glossmann H, Stenirri S, Carrera P, and others. 2000. Three new familial hemiplegic migraine mutants affect P/Q-type Ca(2+) channel kinetics. J Biol Chem275:9239-9243.
32.
Laube GG, Roper J, Pitt JC, Sewing S, Kistner U, Garner CC, and others. 1996. Ultrastructural localization of Shaker-related potassium channel subunits and synapse-associated protein 90 to septate-like junctions in rat cerebellar Pinceaux. Brain Res Mol Brain Res42:51-61.
33.
Lehmann-Horn F, Jurkat-Rott K. 1999. Voltage-gated ion channels and hereditary disease. Physiol Rev79:1317-1372.
34.
Lorenzon NM, Lutz CM, Frankel WN, Beam KG. 1998. Altered calcium channel currents in Purkinje cells of the neurological mutant mouse leaner. J Neurosci18:3382-3389.
35.
Lubbers WJ, Brunt ER, Scheffer H, Litt M, Stulp R, Browne D, and others. 1995. Hereditary myokymia and paroxysmal ataxia linked to chromosome 12 is responsive to acetazolamide. J Neurol Neurosurg Psychiatry59:400-405.
36.
Ophoff RA, Terwindt GM, Vergouwe MN, van Eijk R, Oefner PJ, Hoffman SM, and others. 1996. Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2+ channel gene CACNL1A4. Cell887:543-553.
37.
Pongs O. 1999. Voltage-gated potassium channels: from hyperexcitability to excitement. FEBS Lett452:31-35.
38.
Randall A, Benham CD. 1999. Recent advances in the molecular understanding of voltage-gated Ca2+ channels. Mol Cell Neurosci14:255-272.
39.
Ruppersberg JP, Schroter KH, Sakmann B, Stocker M, Sewing S, Pongs O. 1990. Heteromultimeric channels formed by rat brain potassium-channel proteins. Nature345:535-537.
40.
Sappey-Marinier D, Vighetto A, Peyron R, Broussolle E, Bonmartin A. 1999. Phosphorus and proton magnetic resonance spectroscopy in episodic ataxia type 2. Ann Neurol46:256-259.
41.
Scheffer H, Brunt ER, Mol GJ, van der Vlies P, Stulp RP, Verlind E, and others. 1998. Three novel KCNA1 mutations in episodic ataxia type 1 families. Hum Genet102:464-466.
42.
Smart SL, Lopantsev V, Zhang CL, Robbins CA, Wang H, Chiu SY, and others. 1998. Deletion of the K(V)1.1 potassium channel causes epilepsy in mice. Neuron20:809-819.
43.
Southan AP, Robertson B. 1998. Modulatoin of inhibitory post-synaptic currents (IPSCs) in mouse cerebellar Purkinje and basket cells by snake and scorpion toxin K+ channel blockers. Br J Pharmacol125:1375-1381.
44.
Spauschus A, Eunson L, Hanna MG, Kullmann DM. 1999. Functional characterization of a novel mutation in KCNA1 in episodic ataxia type 1 associated with epilepsy. Ann N Y Acad Sci868:442-446.
Tombaugh GC, Somjen GG. 1996. Effects of extracellular pH on voltage-gated Na+, K+ and Ca2+ currents in isolated rat CA1 neurons. J Physiol (Lond)493:719-732.
47.
Veh RW, Lichtinghagen R, Sewing S, Wunder F, Grumbach IM, Pongs O. 1995. Immunohistochemical localization of five members of the Kv1 channel subunits: contrasting subcellular locations and neuron-specific co-localizations in rat brain. Eur J Neurosci7:2189-2205.
48.
Wakamori M, Yamazaki K, Matsunodaira H, Teramoto T, Tanaka I, Niidome T, and others. 1998. Single tottering mutations responsible for the neuropathic phenotype of the P-type calcium channel. J Biol Chem273:34857-34867.
49.
Wang H, Kunkel DD, Martin TM, Schwartzkroin PA, Tempel BL. 1993. Heteromultimeric K+ channels in terminal and juxtaparanodal regions of neurons. Nature365:75-79.
50.
Wang H, Kunkel DD, Schwartzkroin PA, Tempel BL. 1994. Localization of Kv1.1 and Kv1.2, two K channel proteins, to synaptic terminals, somata, and dendrites in the mouse brain. J Neurosci14:4588-4599.
51.
Wei X, Neely A, Lacerda AE, Olcese R, Stefani E, Perez-Reyes E, and others. 1994. Modification of Ca2+ channel activity by deletions at the carboxyl terminus of the cardiac alpha 1 subunit. J Biol Chem269:1635-1640.
52.
Westenbroek RE, Sakurai T, Elliott EM, Hell JW, Starr TV, Snutch T, and others. 1995. Immunochemical identification and subcellular distribution of the alpha 1a subunits of brain calcium channels. J Neurosci15:6403-6418.
53.
Zerr P, Adelman JP, Maylie J. 1998a. Characterization of three episodic ataxia mutations in the human Kv1.1 potassium channel. FEBS Lett431:461-464.
54.
Zerr P, Adelman JP, Maylie J. 1998b. Episodic ataxia mutations in Kv1.1 alter potassium channel function by dominant negative effects or haploinsufficiency. J Neurosci18:2842-2848.
55.
Zhang CL, Messing A, Chiu SY. 1999. Specific alteration of spontaneous GABAergic inhibition in cerebellar Purkinje cells in mice lacking the potassium channel Kv1.1. J Neurosci19:2852-2864.
56.
Zhou L, Zhang CL, Messing A, Chiu SY. 1998. Temperature-sensitive neuromuscular transmission in Kv1.1 null mice: role of potassium channels under the myelin sheath in young nerves. J Neurosci18:7200-7215.
57.
Zhuchenko O, Bailey J, Bonnen P, Ashizawa T, Stockton DW, Amos C, and others. 1997. Autosomal dominant cerebellar ataxia (SCA6) associated with small polyglutamine expansions in the alpha 1A-voltage-dependent calcium channel. Nat Genet15:62-69.
58.
Zuberi SM, Eunson LH, Spauschus A, De Silva R, Tolmie J, Wood NW, and others. 1999. A novel mutation in the human voltage-gated potassium channel gene (Kv1.1) associates with episodic ataxia type 1 and sometimes with partial epilepsy. Brain122:817-825.
