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. 1998 Aug;75(2):785–792. doi: 10.1016/S0006-3495(98)77568-X

Activation and inactivation of homomeric KvLQT1 potassium channels.

M Pusch 1, R Magrassi 1, B Wollnik 1, F Conti 1
PMCID: PMC1299753  PMID: 9675180

Abstract

The voltage-gated potassium channel protein KvLQT1 (Wang et al., 1996. Nature Genet. 12:17-23) is believed to underlie the delayed rectifier potassium current of cardiac muscle together with the small membrane protein minK (also named IsK) as an essential auxiliary subunit (Barhanin et al., 1996. Nature. 384:78-80; Sanguinetti et al., 1996. Nature. 384:80-83) Using the Xenopus oocyte expression system, we analyzed in detail the gating characteristics of homomeric KvLQT1 channels and of heteromeric KvLQT1/minK channels using two-electrode voltage-clamp recordings. Activation of homomeric KvLQT1 at positive voltages is accompanied by an inactivation process that is revealed by a transient increase in conductance after membrane repolarization to negative values. We studied the recovery from inactivation and the deactivation of the channels during tail repolarizations at -120 mV after conditioning pulses of variable amplitude and duration. Most measurements were made in high extracellular potassium to increase the size of inward tail currents. However, experiments in normal low-potassium solutions showed that, in contrast to classical C-type inactivation, the inactivation of KvLQT1 is independent of extracellular potassium. At +40 mV inactivation develops with a delay of 100 ms. At the same potential, the activation estimated from the amplitude of the late exponential decay of the tail currents follows a less sigmoidal time course, with a late time constant of 300 ms. Inactivation of KvLQT1 is not complete, even at the most positive voltages. The delayed, voltage-dependent onset and the incompleteness of inactivation suggest a sequential gating scheme containing at least two open states and ending with an inactivating step that is voltage independent. In coexpression experiments of KvLQT1 with minK, inactivation seems to be largely absent, although biphasic tails are also observed that could be related to similar phenomena.

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Selected References

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  1. Balser J. R., Bennett P. B., Roden D. M. Time-dependent outward current in guinea pig ventricular myocytes. Gating kinetics of the delayed rectifier. J Gen Physiol. 1990 Oct;96(4):835–863. doi: 10.1085/jgp.96.4.835. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Barhanin J., Lesage F., Guillemare E., Fink M., Lazdunski M., Romey G. K(V)LQT1 and lsK (minK) proteins associate to form the I(Ks) cardiac potassium current. Nature. 1996 Nov 7;384(6604):78–80. doi: 10.1038/384078a0. [DOI] [PubMed] [Google Scholar]
  3. 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]
  4. Campbell D. L., Rasmusson R. L., Strauss H. C. Ionic current mechanisms generating vertebrate primary cardiac pacemaker activity at the single cell level: an integrative view. Annu Rev Physiol. 1992;54:279–302. doi: 10.1146/annurev.ph.54.030192.001431. [DOI] [PubMed] [Google Scholar]
  5. Chouabe C., Neyroud N., Guicheney P., Lazdunski M., Romey G., Barhanin J. Properties of KvLQT1 K+ channel mutations in Romano-Ward and Jervell and Lange-Nielsen inherited cardiac arrhythmias. EMBO J. 1997 Sep 1;16(17):5472–5479. doi: 10.1093/emboj/16.17.5472. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Curran M. E., Splawski I., Timothy K. W., Vincent G. M., Green E. D., Keating M. T. A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome. Cell. 1995 Mar 10;80(5):795–803. doi: 10.1016/0092-8674(95)90358-5. [DOI] [PubMed] [Google Scholar]
  7. DiFrancesco D. The cardiac hyperpolarizing-activated current, if. Origins and developments. Prog Biophys Mol Biol. 1985;46(3):163–183. doi: 10.1016/0079-6107(85)90008-2. [DOI] [PubMed] [Google Scholar]
  8. Goldstein S. A., Miller C. Site-specific mutations in a minimal voltage-dependent K+ channel alter ion selectivity and open-channel block. Neuron. 1991 Sep;7(3):403–408. doi: 10.1016/0896-6273(91)90292-8. [DOI] [PubMed] [Google Scholar]
  9. 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]
  10. Jurkiewicz N. K., Sanguinetti M. C. Rate-dependent prolongation of cardiac action potentials by a methanesulfonanilide class III antiarrhythmic agent. Specific block of rapidly activating delayed rectifier K+ current by dofetilide. Circ Res. 1993 Jan;72(1):75–83. doi: 10.1161/01.res.72.1.75. [DOI] [PubMed] [Google Scholar]
  11. Kaczmarek L. K., Blumenthal E. M. Properties and regulation of the minK potassium channel protein. Physiol Rev. 1997 Jul;77(3):627–641. doi: 10.1152/physrev.1997.77.3.627. [DOI] [PubMed] [Google Scholar]
  12. 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]
  13. McDonald T. V., Yu Z., Ming Z., Palma E., Meyers M. B., Wang K. W., Goldstein S. A., Fishman G. I. A minK-HERG complex regulates the cardiac potassium current I(Kr). Nature. 1997 Jul 17;388(6639):289–292. doi: 10.1038/40882. [DOI] [PubMed] [Google Scholar]
  14. Neyroud N., Tesson F., Denjoy I., Leibovici M., Donger C., Barhanin J., Fauré S., Gary F., Coumel P., Petit C. A novel mutation in the potassium channel gene KVLQT1 causes the Jervell and Lange-Nielsen cardioauditory syndrome. Nat Genet. 1997 Feb;15(2):186–189. doi: 10.1038/ng0297-186. [DOI] [PubMed] [Google Scholar]
  15. Noble D. The surprising heart: a review of recent progress in cardiac electrophysiology. J Physiol. 1984 Aug;353:1–50. doi: 10.1113/jphysiol.1984.sp015320. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Roden D. M., George A. L., Jr The cardiac ion channels: relevance to management of arrhythmias. Annu Rev Med. 1996;47:135–148. doi: 10.1146/annurev.med.47.1.135. [DOI] [PubMed] [Google Scholar]
  18. Romey G., Attali B., Chouabe C., Abitbol I., Guillemare E., Barhanin J., Lazdunski M. Molecular mechanism and functional significance of the MinK control of the KvLQT1 channel activity. J Biol Chem. 1997 Jul 4;272(27):16713–16716. doi: 10.1074/jbc.272.27.16713. [DOI] [PubMed] [Google Scholar]
  19. Russell M. W., Dick M., 2nd, Collins F. S., Brody L. C. KVLQT1 mutations in three families with familial or sporadic long QT syndrome. Hum Mol Genet. 1996 Sep;5(9):1319–1324. doi: 10.1093/hmg/5.9.1319. [DOI] [PubMed] [Google Scholar]
  20. Sanguinetti M. C., Curran M. E., Zou A., Shen J., Spector P. S., Atkinson D. L., Keating M. T. Coassembly of K(V)LQT1 and minK (IsK) proteins to form cardiac I(Ks) potassium channel. Nature. 1996 Nov 7;384(6604):80–83. doi: 10.1038/384080a0. [DOI] [PubMed] [Google Scholar]
  21. Sanguinetti M. C., Jiang C., Curran M. E., Keating M. T. A mechanistic link between an inherited and an acquired cardiac arrhythmia: HERG encodes the IKr potassium channel. Cell. 1995 Apr 21;81(2):299–307. doi: 10.1016/0092-8674(95)90340-2. [DOI] [PubMed] [Google Scholar]
  22. Schulze-Bahr E., Wang Q., Wedekind H., Haverkamp W., Chen Q., Sun Y., Rubie C., Hördt M., Towbin J. A., Borggrefe M. KCNE1 mutations cause jervell and Lange-Nielsen syndrome. Nat Genet. 1997 Nov;17(3):267–268. doi: 10.1038/ng1197-267. [DOI] [PubMed] [Google Scholar]
  23. Schönherr R., Heinemann S. H. Molecular determinants for activation and inactivation of HERG, a human inward rectifier potassium channel. J Physiol. 1996 Jun 15;493(Pt 3):635–642. doi: 10.1113/jphysiol.1996.sp021410. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Smith P. L., Baukrowitz T., Yellen G. The inward rectification mechanism of the HERG cardiac potassium channel. Nature. 1996 Feb 29;379(6568):833–836. doi: 10.1038/379833a0. [DOI] [PubMed] [Google Scholar]
  25. Spector P. S., Curran M. E., Zou A., Keating M. T., Sanguinetti M. C. Fast inactivation causes rectification of the IKr channel. J Gen Physiol. 1996 May;107(5):611–619. doi: 10.1085/jgp.107.5.611. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Splawski I., Tristani-Firouzi M., Lehmann M. H., Sanguinetti M. C., Keating M. T. Mutations in the hminK gene cause long QT syndrome and suppress IKs function. Nat Genet. 1997 Nov;17(3):338–340. doi: 10.1038/ng1197-338. [DOI] [PubMed] [Google Scholar]
  27. Tai K. K., Goldstein S. A. The conduction pore of a cardiac potassium channel. Nature. 1998 Feb 5;391(6667):605–608. doi: 10.1038/35416. [DOI] [PubMed] [Google Scholar]
  28. Takumi T., Ohkubo H., Nakanishi S. Cloning of a membrane protein that induces a slow voltage-gated potassium current. Science. 1988 Nov 18;242(4881):1042–1045. doi: 10.1126/science.3194754. [DOI] [PubMed] [Google Scholar]
  29. Tanaka T., Nagai R., Tomoike H., Takata S., Yano K., Yabuta K., Haneda N., Nakano O., Shibata A., Sawayama T. Four novel KVLQT1 and four novel HERG mutations in familial long-QT syndrome. Circulation. 1997 Feb 4;95(3):565–567. doi: 10.1161/01.cir.95.3.565. [DOI] [PubMed] [Google Scholar]
  30. Trudeau M. C., Warmke J. W., Ganetzky B., Robertson G. A. HERG, a human inward rectifier in the voltage-gated potassium channel family. Science. 1995 Jul 7;269(5220):92–95. doi: 10.1126/science.7604285. [DOI] [PubMed] [Google Scholar]
  31. Wang Q., Curran M. E., Splawski I., Burn T. C., Millholland J. M., VanRaay T. J., Shen J., Timothy K. W., Vincent G. M., de Jager T. Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias. Nat Genet. 1996 Jan;12(1):17–23. doi: 10.1038/ng0196-17. [DOI] [PubMed] [Google Scholar]
  32. Wang S., Liu S., Morales M. J., Strauss H. C., Rasmusson R. L. A quantitative analysis of the activation and inactivation kinetics of HERG expressed in Xenopus oocytes. J Physiol. 1997 Jul 1;502(Pt 1):45–60. doi: 10.1111/j.1469-7793.1997.045bl.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Wang S., Morales M. J., Liu S., Strauss H. C., Rasmusson R. L. Time, voltage and ionic concentration dependence of rectification of h-erg expressed in Xenopus oocytes. FEBS Lett. 1996 Jul 1;389(2):167–173. doi: 10.1016/0014-5793(96)00570-4. [DOI] [PubMed] [Google Scholar]
  34. Wollnik B., Schroeder B. C., Kubisch C., Esperer H. D., Wieacker P., Jentsch T. J. Pathophysiological mechanisms of dominant and recessive KVLQT1 K+ channel mutations found in inherited cardiac arrhythmias. Hum Mol Genet. 1997 Oct;6(11):1943–1949. doi: 10.1093/hmg/6.11.1943. [DOI] [PubMed] [Google Scholar]
  35. Yang W. P., Levesque P. C., Little W. A., Conder M. L., Shalaby F. Y., Blanar M. A. KvLQT1, a voltage-gated potassium channel responsible for human cardiac arrhythmias. Proc Natl Acad Sci U S A. 1997 Apr 15;94(8):4017–4021. doi: 10.1073/pnas.94.8.4017. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. van den Berg M. H., Wilde A. A., Robles de Medina E. O., Meyer H., Geelen J. L., Jongbloed R. J., Wellens H. J., Geraedts J. P. The long QT syndrome: a novel missense mutation in the S6 region of the KVLQT1 gene. Hum Genet. 1997 Sep;100(3-4):356–361. doi: 10.1007/s004390050516. [DOI] [PubMed] [Google Scholar]

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