Skip to main content
NCBI home page
The Journal of General Physiology logoLink to The Journal of General Physiology
. 1996 Feb 1;107(2):183–194. doi: 10.1085/jgp.107.2.183

Paramyotonia congenita mutations reveal different roles for segments S3 and S4 of domain D4 in hSkM1 sodium channel gating

PMCID: PMC2219264  PMID: 8833340

Abstract

Mutations in the gene encoding the voltage-gated sodium channel of skeletal muscle (SkMl) have been identified in a group of autosomal dominant diseases, characterized by abnormalities of the sarcolemmal excitability, that include paramyotonia congenita (PC) and hyperkalemic periodic paralysis (HYPP). We previously reported that PC mutations cause in common a slowing of inactivation in the human SkMl sodium channel. In this investigation, we examined the molecular mechanisms responsible for the effects of L1433R, located in D4/S3, on channel gating by creating a series of additional mutations at the 1433 site. Unlike the R1448C mutation, found in D4/S4, which produces its effects largely due to the loss of the positive charge, change of the hydropathy of the side chain rather than charge is the primary factor mediating the effects of L1433R. These two mutations also differ in their effects on recovery from inactivation, conditioned inactivation, and steady state inactivation of the hSkMl channels. We constructed a double mutation containing both L1433R and R1448C. The double mutation closely resembled R1448C with respect to alterations in the kinetics of inactivation during depolarization and voltage dependence, but was indistinguishable from L1433R in the kinetics of recovery from inactivation and steady state inactivation. No additive effects were seen, suggesting that these two segments interact during gating. In addition, we found that these mutations have different effects on the delay of recovery from inactivation and the kinetics of the tail currents, raising a question whether this delay is a reflection of the deactivation process. These results suggest that the S3 and S4 segments play distinct roles in different processes of hSkM1 channel gating: D4/S4 is critical for the deactivation and inactivation of the open channel while D4/S3 has a dominant role in the recovery of inactivated channels. However, these two segments interact during the entry to, and exit from, inactivation states.

Full Text

The Full Text of this article is available as a PDF (1,016.0 KB).

Selected References

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

  1. 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]
  2. Barchi R. L. Molecular pathology of the skeletal muscle sodium channel. Annu Rev Physiol. 1995;57:355–385. doi: 10.1146/annurev.ph.57.030195.002035. [DOI] [PubMed] [Google Scholar]
  3. Bezanilla F., Armstrong C. M. Inactivation of the sodium channel. I. Sodium current experiments. J Gen Physiol. 1977 Nov;70(5):549–566. doi: 10.1085/jgp.70.5.549. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Blaber M., Zhang X. J., Matthews B. W. Structural basis of amino acid alpha helix propensity. Science. 1993 Jun 11;260(5114):1637–1640. doi: 10.1126/science.8503008. [DOI] [PubMed] [Google Scholar]
  5. Cannon S. C., Strittmatter S. M. Functional expression of sodium channel mutations identified in families with periodic paralysis. Neuron. 1993 Feb;10(2):317–326. doi: 10.1016/0896-6273(93)90321-h. [DOI] [PubMed] [Google Scholar]
  6. Chahine M., George A. L., Jr, Zhou M., Ji S., Sun W., Barchi R. L., Horn R. Sodium channel mutations in paramyotonia congenita uncouple inactivation from activation. Neuron. 1994 Feb;12(2):281–294. doi: 10.1016/0896-6273(94)90271-2. [DOI] [PubMed] [Google Scholar]
  7. Cummins T. R., Zhou J., Sigworth F. J., Ukomadu C., Stephan M., Ptácek L. J., Agnew W. S. Functional consequences of a Na+ channel mutation causing hyperkalemic periodic paralysis. Neuron. 1993 Apr;10(4):667–678. doi: 10.1016/0896-6273(93)90168-q. [DOI] [PubMed] [Google Scholar]
  8. Durell S. R., Guy H. R. Atomic scale structure and functional models of voltage-gated potassium channels. Biophys J. 1992 Apr;62(1):238–250. doi: 10.1016/S0006-3495(92)81809-X. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. George A. L., Jr, Komisarof J., Kallen R. G., Barchi R. L. Primary structure of the adult human skeletal muscle voltage-dependent sodium channel. Ann Neurol. 1992 Feb;31(2):131–137. doi: 10.1002/ana.410310203. [DOI] [PubMed] [Google Scholar]
  10. Guy H. R., Seetharamulu P. Molecular model of the action potential sodium channel. Proc Natl Acad Sci U S A. 1986 Jan;83(2):508–512. doi: 10.1073/pnas.83.2.508. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Hamill O. P., Marty A., Neher E., Sakmann B., Sigworth F. J. Improved patch-clamp techniques for high-resolution current recording from cells and cell-free membrane patches. Pflugers Arch. 1981 Aug;391(2):85–100. doi: 10.1007/BF00656997. [DOI] [PubMed] [Google Scholar]
  12. Horn R., Patlak J., Stevens C. F. Sodium channels need not open before they inactivate. Nature. 1981 Jun 4;291(5814):426–427. doi: 10.1038/291426a0. [DOI] [PubMed] [Google Scholar]
  13. Keynes R. D. The kinetics of voltage-gated ion channels. Q Rev Biophys. 1994 Dec;27(4):339–434. doi: 10.1017/s0033583500003097. [DOI] [PubMed] [Google Scholar]
  14. Kuo C. C., Bean B. P. Na+ channels must deactivate to recover from inactivation. Neuron. 1994 Apr;12(4):819–829. doi: 10.1016/0896-6273(94)90335-2. [DOI] [PubMed] [Google Scholar]
  15. Kyte J., Doolittle R. F. A simple method for displaying the hydropathic character of a protein. J Mol Biol. 1982 May 5;157(1):105–132. doi: 10.1016/0022-2836(82)90515-0. [DOI] [PubMed] [Google Scholar]
  16. O'Leary M. E., Chen L. Q., Kallen R. G., Horn R. A molecular link between activation and inactivation of sodium channels. J Gen Physiol. 1995 Oct;106(4):641–658. doi: 10.1085/jgp.106.4.641. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Patlak J. Molecular kinetics of voltage-dependent Na+ channels. Physiol Rev. 1991 Oct;71(4):1047–1080. doi: 10.1152/physrev.1991.71.4.1047. [DOI] [PubMed] [Google Scholar]
  18. Ptacek L. J., Gouw L., Kwieciński H., McManis P., Mendell J. R., Barohn R. J., George A. L., Jr, Barchi R. L., Robertson M., Leppert M. F. Sodium channel mutations in paramyotonia congenita and hyperkalemic periodic paralysis. Ann Neurol. 1993 Mar;33(3):300–307. doi: 10.1002/ana.410330312. [DOI] [PubMed] [Google Scholar]
  19. Ptácek L. J., George A. L., Jr, Barchi R. L., Griggs R. C., Riggs J. E., Robertson M., Leppert M. F. Mutations in an S4 segment of the adult skeletal muscle sodium channel cause paramyotonia congenita. Neuron. 1992 May;8(5):891–897. doi: 10.1016/0896-6273(92)90203-p. [DOI] [PubMed] [Google Scholar]
  20. Yang N., Horn R. Evidence for voltage-dependent S4 movement in sodium channels. Neuron. 1995 Jul;15(1):213–218. doi: 10.1016/0896-6273(95)90078-0. [DOI] [PubMed] [Google Scholar]
  21. Yang N., Ji S., Zhou M., Ptácek L. J., Barchi R. L., Horn R., George A. L., Jr Sodium channel mutations in paramyotonia congenita exhibit similar biophysical phenotypes in vitro. Proc Natl Acad Sci U S A. 1994 Dec 20;91(26):12785–12789. doi: 10.1073/pnas.91.26.12785. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from The Journal of General Physiology are provided here courtesy of The Rockefeller University Press

RESOURCES