Skip to main content
PMC home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1992 Jan 15;89(2):554–558. doi: 10.1073/pnas.89.2.554

Primary structure and functional expression of the human cardiac tetrodotoxin-insensitive voltage-dependent sodium channel.

M E Gellens 1, A L George Jr 1, L Q Chen 1, M Chahine 1, R Horn 1, R L Barchi 1, R G Kallen 1
PMCID: PMC48277  PMID: 1309946

Abstract

The principal voltage-sensitive sodium channel from human heart has been cloned, sequenced, and functionally expressed. The cDNA, designated hH1, encodes a 2016-amino acid protein that is homologous to other members of the sodium channel multigene family and bears greater than 90% identity to the tetrodotoxin-insensitive sodium channel characteristic of rat heart and of immature and denervated rat skeletal muscle. Northern blot analysis demonstrates an approximately 9.0-kilobase transcript expressed in human atrial and ventricular cardiac muscle but not in adult skeletal muscle, brain, myometrium, liver, or spleen. When expressed in Xenopus oocytes, hH1 exhibits rapid activation and inactivation kinetics similar to native cardiac sodium channels. The single channel conductance of hH1 to sodium ions is about twice that of the homologous rat channel and hH1 is more resistant to block by tetrodotoxin (IC50 = 5.7 microM). hH1 is also resistant to mu-conotoxin but sensitive to block by therapeutic concentrations of lidocaine in a use-dependent manner.

Full text

PDF
554

Images in this article

555Image
on p.555
556Image
on p.556

Selected References

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

  1. Auld V. J., Goldin A. L., Krafte D. S., Marshall J., Dunn J. M., Catterall W. A., Lester H. A., Davidson N., Dunn R. J. A rat brain Na+ channel alpha subunit with novel gating properties. Neuron. 1988 Aug;1(6):449–461. doi: 10.1016/0896-6273(88)90176-6. [DOI] [PubMed] [Google Scholar]
  2. Bean B. P., Cohen C. J., Tsien R. W. Lidocaine block of cardiac sodium channels. J Gen Physiol. 1983 May;81(5):613–642. doi: 10.1085/jgp.81.5.613. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Brown A. M., Lee K. S., Powell T. Voltage clamp and internal perfusion of single rat heart muscle cells. J Physiol. 1981 Sep;318:455–477. doi: 10.1113/jphysiol.1981.sp013878. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Cachelin A. B., De Peyer J. E., Kokubun S., Reuter H. Sodium channels in cultured cardiac cells. J Physiol. 1983 Jul;340:389–401. doi: 10.1113/jphysiol.1983.sp014768. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Chirgwin J. M., Przybyla A. E., MacDonald R. J., Rutter W. J. Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry. 1979 Nov 27;18(24):5294–5299. doi: 10.1021/bi00591a005. [DOI] [PubMed] [Google Scholar]
  6. Cohen C. J., Bean B. P., Colatsky T. J., Tsien R. W. Tetrodotoxin block of sodium channels in rabbit Purkinje fibers. Interactions between toxin binding and channel gating. J Gen Physiol. 1981 Oct;78(4):383–411. doi: 10.1085/jgp.78.4.383. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Cruz L. J., Gray W. R., Olivera B. M., Zeikus R. D., Kerr L., Yoshikami D., Moczydlowski E. Conus geographus toxins that discriminate between neuronal and muscle sodium channels. J Biol Chem. 1985 Aug 5;260(16):9280–9288. [PubMed] [Google Scholar]
  8. George A. L., Jr, Ledbetter D. H., Kallen R. G., Barchi R. L. Assignment of a human skeletal muscle sodium channel alpha-subunit gene (SCN4A) to 17q23.1-25.3. Genomics. 1991 Mar;9(3):555–556. doi: 10.1016/0888-7543(91)90425-e. [DOI] [PubMed] [Google Scholar]
  9. Guy H. R., Conti F. Pursuing the structure and function of voltage-gated channels. Trends Neurosci. 1990 Jun;13(6):201–206. doi: 10.1016/0166-2236(90)90160-c. [DOI] [PubMed] [Google Scholar]
  10. Haimovich B., Schotland D. L., Fieles W. E., Barchi R. L. Localization of sodium channel subtypes in adult rat skeletal muscle using channel-specific monoclonal antibodies. J Neurosci. 1987 Sep;7(9):2957–2966. doi: 10.1523/JNEUROSCI.07-09-02957.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Harris J. B., Thesleff S. Studies on tetrodotoxin resistant action potentials in denervated skeletal muscle. Acta Physiol Scand. 1971 Nov;83(3):382–388. doi: 10.1111/j.1748-1716.1971.tb05091.x. [DOI] [PubMed] [Google Scholar]
  12. Kallen R. G., Sheng Z. H., Yang J., Chen L. Q., Rogart R. B., Barchi R. L. Primary structure and expression of a sodium channel characteristic of denervated and immature rat skeletal muscle. Neuron. 1990 Feb;4(2):233–242. doi: 10.1016/0896-6273(90)90098-z. [DOI] [PubMed] [Google Scholar]
  13. Krafte D. S., Volberg W. A., Dillon K., Ezrin A. M. Expression of cardiac Na channels with appropriate physiological and pharmacological properties in Xenopus oocytes. Proc Natl Acad Sci U S A. 1991 May 15;88(10):4071–4074. doi: 10.1073/pnas.88.10.4071. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Kunze D. L., Lacerda A. E., Wilson D. L., Brown A. M. Cardiac Na currents and the inactivating, reopening, and waiting properties of single cardiac Na channels. J Gen Physiol. 1985 Nov;86(5):691–719. doi: 10.1085/jgp.86.5.691. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Litt M., Luty J., Kwak M., Allen L., Magenis R. E., Mandel G. Localization of a human brain sodium channel gene (SCN2A) to chromosome 2. Genomics. 1989 Aug;5(2):204–208. doi: 10.1016/0888-7543(89)90047-5. [DOI] [PubMed] [Google Scholar]
  16. Methfessel C., Witzemann V., Takahashi T., Mishina M., Numa S., Sakmann B. Patch clamp measurements on Xenopus laevis oocytes: currents through endogenous channels and implanted acetylcholine receptor and sodium channels. Pflugers Arch. 1986 Dec;407(6):577–588. doi: 10.1007/BF00582635. [DOI] [PubMed] [Google Scholar]
  17. Noda M., Suzuki H., Numa S., Stühmer W. A single point mutation confers tetrodotoxin and saxitoxin insensitivity on the sodium channel II. FEBS Lett. 1989 Dec 18;259(1):213–216. doi: 10.1016/0014-5793(89)81531-5. [DOI] [PubMed] [Google Scholar]
  18. Pappone P. A. Voltage-clamp experiments in normal and denervated mammalian skeletal muscle fibres. J Physiol. 1980 Sep;306:377–410. doi: 10.1113/jphysiol.1980.sp013403. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Rogart R. B., Cribbs L. L., Muglia L. K., Kephart D. D., Kaiser M. W. Molecular cloning of a putative tetrodotoxin-resistant rat heart Na+ channel isoform. Proc Natl Acad Sci U S A. 1989 Oct;86(20):8170–8174. doi: 10.1073/pnas.86.20.8170. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Rogart R. B. High-STX-affinity vs. low-STX-affinity Na+ channel subtypes in nerve, heart, and skeletal muscle. Ann N Y Acad Sci. 1986;479:402–430. doi: 10.1111/j.1749-6632.1986.tb15585.x. [DOI] [PubMed] [Google Scholar]
  21. Scheuer T., Auld V. J., Boyd S., Offord J., Dunn R., Catterall W. A. Functional properties of rat brain sodium channels expressed in a somatic cell line. Science. 1990 Feb 16;247(4944):854–858. doi: 10.1126/science.2154850. [DOI] [PubMed] [Google Scholar]
  22. Sutton F., Davidson N., Lester H. A. Tetrodotoxin-sensitive voltage-dependent Na currents recorded from Xenopus oocytes injected with mammalian cardiac muscle RNA. Brain Res. 1988 Apr;427(2):187–191. doi: 10.1016/0169-328x(88)90065-4. [DOI] [PubMed] [Google Scholar]
  23. Tomaselli G. F., Feldman A. M., Yellen G., Marban E. Human cardiac sodium channels expressed in Xenopus oocytes. Am J Physiol. 1990 Mar;258(3 Pt 2):H903–H906. doi: 10.1152/ajpheart.1990.258.3.H903. [DOI] [PubMed] [Google Scholar]
  24. Trimmer J. S., Agnew W. S. Molecular diversity of voltage-sensitive Na channels. Annu Rev Physiol. 1989;51:401–418. doi: 10.1146/annurev.ph.51.030189.002153. [DOI] [PubMed] [Google Scholar]
  25. Trimmer J. S., Cooperman S. S., Tomiko S. A., Zhou J. Y., Crean S. M., Boyle M. B., Kallen R. G., Sheng Z. H., Barchi R. L., Sigworth F. J. Primary structure and functional expression of a mammalian skeletal muscle sodium channel. Neuron. 1989 Jul;3(1):33–49. doi: 10.1016/0896-6273(89)90113-x. [DOI] [PubMed] [Google Scholar]
  26. Weiss R. E., Horn R. Functional differences between two classes of sodium channels in developing rat skeletal muscle. Science. 1986 Jul 18;233(4761):361–364. doi: 10.1126/science.2425432. [DOI] [PubMed] [Google Scholar]
  27. White M. M., Chen L. Q., Kleinfield R., Kallen R. G., Barchi R. L. SkM2, a Na+ channel cDNA clone from denervated skeletal muscle, encodes a tetrodotoxin-insensitive Na+ channel. Mol Pharmacol. 1991 May;39(5):604–608. [PubMed] [Google Scholar]
  28. Yamamoto D., Yeh J. Z., Narahashi T. Voltage-dependent calcium block of normal and tetramethrin-modified single sodium channels. Biophys J. 1984 Jan;45(1):337–344. doi: 10.1016/S0006-3495(84)84159-4. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES