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. 1998 Mar 2;17(5):1200–1207. doi: 10.1093/emboj/17.5.1200

Episodic ataxia type-1 mutations in the hKv1.1 cytoplasmic pore region alter the gating properties of the channel.

M C D'Adamo 1, Z Liu 1, J P Adelman 1, J Maylie 1, M Pessia 1
PMCID: PMC1170468  PMID: 9482717

Abstract

Episodic ataxia type-1 is a rare human neurological syndrome which occurs during childhood and persists through the whole life of affected patients. Several heterozygous point mutations have been found in the coding sequence of the voltage-gated potassium channel gene hKv1.1 of different affected families. V408A and E325D mutations are located in the cytoplasmic putative pore region of hKv1.1 channels and profoundly alter their gating properties. V408A channels showed increased kinetic rates of activation, deactivation and C-type inactivation. Expression of E325D channels in Xenopus oocytes led to an approximately 13-fold current amplitude reduction and to a 52.4 mV positive shift in the voltage dependence of activation. Moreover, the E325D mutation altered the kinetics of activation, deactivation, C-type inactivation and channel open probability. Heteromeric channels composed of two wild-type and two mutated subunits, linked as dimers, showed gating properties intermediate between channels formed from four normal or four mutated subunits. The results demonstrate that the highly conserved residues Val408 and Glu325 play a pivotal role in several gating processes of a human potassium channel, and suggest a pathogenetic mechanism by which the impairment of the delayed-rectifier function of affected neurons is related to the type and number of mutated subunits which make up the hKv1.1 channels.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Adelman J. P., Bond C. T., Pessia M., Maylie J. Episodic ataxia results from voltage-dependent potassium channels with altered functions. Neuron. 1995 Dec;15(6):1449–1454. doi: 10.1016/0896-6273(95)90022-5. [DOI] [PubMed] [Google Scholar]
  2. Aldrich R. W., Jr, Getting P. A., Thompson S. H. Mechanism of frequency-dependent broadening of molluscan neurone soma spikes. J Physiol. 1979 Jun;291:531–544. doi: 10.1113/jphysiol.1979.sp012829. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Armstrong C. M., Bezanilla F. Inactivation of the sodium channel. II. Gating current experiments. J Gen Physiol. 1977 Nov;70(5):567–590. doi: 10.1085/jgp.70.5.567. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Baukrowitz T., Yellen G. Modulation of K+ current by frequency and external [K+]: a tale of two inactivation mechanisms. Neuron. 1995 Oct;15(4):951–960. doi: 10.1016/0896-6273(95)90185-x. [DOI] [PubMed] [Google Scholar]
  5. Beckh S., Pongs O. Members of the RCK potassium channel family are differentially expressed in the rat nervous system. EMBO J. 1990 Mar;9(3):777–782. doi: 10.1002/j.1460-2075.1990.tb08173.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Bouchard J. P., Roberge C., van Gelder N. M., Barbeau A. Familial periodic ataxia responsive to acetazolamide. Can J Neurol Sci. 1984 Nov;11(4 Suppl):550–553. doi: 10.1017/s0317167100035022. [DOI] [PubMed] [Google Scholar]
  7. Browne D. L., Brunt E. R., Griggs R. C., Nutt J. G., Gancher S. T., Smith E. A., Litt M. Identification of two new KCNA1 mutations in episodic ataxia/myokymia families. Hum Mol Genet. 1995 Sep;4(9):1671–1672. doi: 10.1093/hmg/4.9.1671. [DOI] [PubMed] [Google Scholar]
  8. Browne D. L., Gancher S. T., Nutt J. G., Brunt E. R., Smith E. A., Kramer P., Litt M. Episodic ataxia/myokymia syndrome is associated with point mutations in the human potassium channel gene, KCNA1. Nat Genet. 1994 Oct;8(2):136–140. doi: 10.1038/ng1094-136. [DOI] [PubMed] [Google Scholar]
  9. Brunt E. R., van Weerden T. W. Familial paroxysmal kinesigenic ataxia and continuous myokymia. Brain. 1990 Oct;113(Pt 5):1361–1382. doi: 10.1093/brain/113.5.1361. [DOI] [PubMed] [Google Scholar]
  10. Choi K. L., Mossman C., Aubé J., Yellen G. The internal quaternary ammonium receptor site of Shaker potassium channels. Neuron. 1993 Mar;10(3):533–541. doi: 10.1016/0896-6273(93)90340-w. [DOI] [PubMed] [Google Scholar]
  11. Christie M. J., North R. A., Osborne P. B., Douglass J., Adelman J. P. Heteropolymeric potassium channels expressed in Xenopus oocytes from cloned subunits. Neuron. 1990 Mar;4(3):405–411. doi: 10.1016/0896-6273(90)90052-h. [DOI] [PubMed] [Google Scholar]
  12. Comu S., Giuliani M., Narayanan V. Episodic ataxia and myokymia syndrome: a new mutation of potassium channel gene Kv1.1. Ann Neurol. 1996 Oct;40(4):684–687. doi: 10.1002/ana.410400422. [DOI] [PubMed] [Google Scholar]
  13. Gancher S. T., Nutt J. G. Autosomal dominant episodic ataxia: a heterogeneous syndrome. Mov Disord. 1986;1(4):239–253. doi: 10.1002/mds.870010404. [DOI] [PubMed] [Google Scholar]
  14. Grissmer S., Cahalan M. TEA prevents inactivation while blocking open K+ channels in human T lymphocytes. Biophys J. 1989 Jan;55(1):203–206. doi: 10.1016/S0006-3495(89)82793-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Horton R. M., Hunt H. D., Ho S. N., Pullen J. K., Pease L. R. Engineering hybrid genes without the use of restriction enzymes: gene splicing by overlap extension. Gene. 1989 Apr 15;77(1):61–68. doi: 10.1016/0378-1119(89)90359-4. [DOI] [PubMed] [Google Scholar]
  16. Hoshi T., Zagotta W. N., Aldrich R. W. Biophysical and molecular mechanisms of Shaker potassium channel inactivation. Science. 1990 Oct 26;250(4980):533–538. doi: 10.1126/science.2122519. [DOI] [PubMed] [Google Scholar]
  17. Hoshi T., Zagotta W. N., Aldrich R. W. Two types of inactivation in Shaker K+ channels: effects of alterations in the carboxy-terminal region. Neuron. 1991 Oct;7(4):547–556. doi: 10.1016/0896-6273(91)90367-9. [DOI] [PubMed] [Google Scholar]
  18. Isacoff E. Y., Jan Y. N., Jan L. Y. Putative receptor for the cytoplasmic inactivation gate in the Shaker K+ channel. Nature. 1991 Sep 5;353(6339):86–90. doi: 10.1038/353086a0. [DOI] [PubMed] [Google Scholar]
  19. Jan Y. N., Jan L. Y., Dennis M. J. Two mutations of synaptic transmission in Drosophila. Proc R Soc Lond B Biol Sci. 1977 Jul 28;198(1130):87–108. doi: 10.1098/rspb.1977.0087. [DOI] [PubMed] [Google Scholar]
  20. Kamb A., Iverson L. E., Tanouye M. A. Molecular characterization of Shaker, a Drosophila gene that encodes a potassium channel. Cell. 1987 Jul 31;50(3):405–413. doi: 10.1016/0092-8674(87)90494-6. [DOI] [PubMed] [Google Scholar]
  21. Kaplan W. D., Trout W. E., 3rd The behavior of four neurological mutants of Drosophila. Genetics. 1969 Feb;61(2):399–409. doi: 10.1093/genetics/61.2.399. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Kavanaugh M. P., Hurst R. S., Yakel J., Varnum M. D., Adelman J. P., North R. A. Multiple subunits of a voltage-dependent potassium channel contribute to the binding site for tetraethylammonium. Neuron. 1992 Mar;8(3):493–497. doi: 10.1016/0896-6273(92)90277-k. [DOI] [PubMed] [Google Scholar]
  23. Litt M., Kramer P., Browne D., Gancher S., Brunt E. R., Root D., Phromchotikul T., Dubay C. J., Nutt J. A gene for episodic ataxia/myokymia maps to chromosome 12p13. Am J Hum Genet. 1994 Oct;55(4):702–709. [PMC free article] [PubMed] [Google Scholar]
  24. Lopez G. A., Jan Y. N., Jan L. Y. Evidence that the S6 segment of the Shaker voltage-gated K+ channel comprises part of the pore. Nature. 1994 Jan 13;367(6459):179–182. doi: 10.1038/367179a0. [DOI] [PubMed] [Google Scholar]
  25. López-Barneo J., Hoshi T., Heinemann S. H., Aldrich R. W. Effects of external cations and mutations in the pore region on C-type inactivation of Shaker potassium channels. Receptors Channels. 1993;1(1):61–71. [PubMed] [Google Scholar]
  26. MacKinnon R. Determination of the subunit stoichiometry of a voltage-activated potassium channel. Nature. 1991 Mar 21;350(6315):232–235. doi: 10.1038/350232a0. [DOI] [PubMed] [Google Scholar]
  27. Molina A., Castellano A. G., López-Barneo J. Pore mutations in Shaker K+ channels distinguish between the sites of tetraethylammonium blockade and C-type inactivation. J Physiol. 1997 Mar 1;499(Pt 2):361–367. doi: 10.1113/jphysiol.1997.sp021933. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Ophoff R. A., Terwindt G. M., Vergouwe M. N., van Eijk R., Oefner P. J., Hoffman S. M., Lamerdin J. E., Mohrenweiser H. W., Bulman D. E., Ferrari M. Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2+ channel gene CACNL1A4. Cell. 1996 Nov 1;87(3):543–552. doi: 10.1016/s0092-8674(00)81373-2. [DOI] [PubMed] [Google Scholar]
  29. Pardo L. A., Heinemann S. H., Terlau H., Ludewig U., Lorra C., Pongs O., Stühmer W. Extracellular K+ specifically modulates a rat brain K+ channel. Proc Natl Acad Sci U S A. 1992 Mar 15;89(6):2466–2470. doi: 10.1073/pnas.89.6.2466. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Ruppersberg J. P., Schröter K. H., Sakmann B., Stocker M., Sewing S., Pongs O. Heteromultimeric channels formed by rat brain potassium-channel proteins. Nature. 1990 Jun 7;345(6275):535–537. doi: 10.1038/345535a0. [DOI] [PubMed] [Google Scholar]
  31. Salkoff L., Wyman R. Genetic modification of potassium channels in Drosophila Shaker mutants. Nature. 1981 Sep 17;293(5829):228–230. doi: 10.1038/293228a0. [DOI] [PubMed] [Google Scholar]
  32. Slesinger P. A., Jan Y. N., Jan L. Y. The S4-S5 loop contributes to the ion-selective pore of potassium channels. Neuron. 1993 Oct;11(4):739–749. doi: 10.1016/0896-6273(93)90083-4. [DOI] [PubMed] [Google Scholar]
  33. Stühmer W., Ruppersberg J. P., Schröter K. H., Sakmann B., Stocker M., Giese K. P., Perschke A., Baumann A., Pongs O. Molecular basis of functional diversity of voltage-gated potassium channels in mammalian brain. EMBO J. 1989 Nov;8(11):3235–3244. doi: 10.1002/j.1460-2075.1989.tb08483.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Tanouye M. A., Ferrus A. Action potentials in normal and Shaker mutant Drosophila. J Neurogenet. 1985 Sep;2(4):253–271. doi: 10.3109/01677068509102322. [DOI] [PubMed] [Google Scholar]
  35. VanDyke D. H., Griggs R. C., Murphy M. J., Goldstein M. N. Hereditary myokymia and periodic ataxia. J Neurol Sci. 1975 May;25(1):109–118. doi: 10.1016/0022-510x(75)90191-4. [DOI] [PubMed] [Google Scholar]
  36. Wang H., Kunkel D. D., Martin T. M., Schwartzkroin P. A., Tempel B. L. Heteromultimeric K+ channels in terminal and juxtaparanodal regions of neurons. Nature. 1993 Sep 2;365(6441):75–79. doi: 10.1038/365075a0. [DOI] [PubMed] [Google Scholar]
  37. Wang H., Kunkel D. D., Schwartzkroin P. A., Tempel B. L. Localization of Kv1.1 and Kv1.2, two K channel proteins, to synaptic terminals, somata, and dendrites in the mouse brain. J Neurosci. 1994 Aug;14(8):4588–4599. doi: 10.1523/JNEUROSCI.14-08-04588.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Zagotta W. N., Hoshi T., Aldrich R. W. Restoration of inactivation in mutants of Shaker potassium channels by a peptide derived from ShB. Science. 1990 Oct 26;250(4980):568–571. doi: 10.1126/science.2122520. [DOI] [PubMed] [Google Scholar]

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