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. 1997 Oct 15;16(20):6066–6076. doi: 10.1093/emboj/16.20.6066

Mutations in the alpha1 subunit of an L-type voltage-activated Ca2+ channel cause myotonia in Caenorhabditis elegans.

R Y Lee 1, L Lobel 1, M Hengartner 1, H R Horvitz 1, L Avery 1
PMCID: PMC1326290  PMID: 9321386

Abstract

The control of excitable cell action potentials is central to animal behavior. We show that the egl-19 gene plays a pivotal role in regulating muscle excitation and contraction in the nematode Caenorhabditis elegans and encodes the alphal subunit of a homologue of vertebrate L-type voltage-activated Ca2+ channels. Semi-dominant, gain-of-function mutations in egl-19 cause myotonia: mutant muscle action potentials are prolonged and the relaxation delayed. Partial loss-of-function mutations cause slow muscle depolarization and feeble contraction. The most severe loss-of-function mutants lack muscle contraction and die as embryos. We localized two myotonic mutations in the sixth membrane-spanning domain of the first repeat (IS6) region, which has been shown to be responsible for voltage-dependent inactivation. A third myotonic mutation implicates IIIS4, a region involved in sensing plasma-membrane voltage change, in the inactivation process.

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Selected References

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  1. Albertson D. G., Thomson J. N. The pharynx of Caenorhabditis elegans. Philos Trans R Soc Lond B Biol Sci. 1976 Aug 10;275(938):299–325. doi: 10.1098/rstb.1976.0085. [DOI] [PubMed] [Google Scholar]
  2. Avery L., Horvitz H. R. Pharyngeal pumping continues after laser killing of the pharyngeal nervous system of C. elegans. Neuron. 1989 Oct;3(4):473–485. doi: 10.1016/0896-6273(89)90206-7. [DOI] [PubMed] [Google Scholar]
  3. Avery L. The genetics of feeding in Caenorhabditis elegans. Genetics. 1993 Apr;133(4):897–917. doi: 10.1093/genetics/133.4.897. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Barstead R. J., Waterston R. H. The basal component of the nematode dense-body is vinculin. J Biol Chem. 1989 Jun 15;264(17):10177–10185. [PubMed] [Google Scholar]
  5. Bean B. P. Classes of calcium channels in vertebrate cells. Annu Rev Physiol. 1989;51:367–384. doi: 10.1146/annurev.ph.51.030189.002055. [DOI] [PubMed] [Google Scholar]
  6. Byerly L., Masuda M. O. Voltage-clamp analysis of the potassium current that produces a negative-going action potential in Ascaris muscle. J Physiol. 1979 Mar;288:263–284. [PMC free article] [PubMed] [Google Scholar]
  7. Catterall W. A. Structure and function of voltage-gated ion channels. Annu Rev Biochem. 1995;64:493–531. doi: 10.1146/annurev.bi.64.070195.002425. [DOI] [PubMed] [Google Scholar]
  8. 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]
  9. Chalfie M., Tu Y., Euskirchen G., Ward W. W., Prasher D. C. Green fluorescent protein as a marker for gene expression. Science. 1994 Feb 11;263(5148):802–805. doi: 10.1126/science.8303295. [DOI] [PubMed] [Google Scholar]
  10. Coulson A., Huynh C., Kozono Y., Shownkeen R. The physical map of the Caenorhabditis elegans genome. Methods Cell Biol. 1995;48:533–550. doi: 10.1016/s0091-679x(08)61402-8. [DOI] [PubMed] [Google Scholar]
  11. Coulson A., Waterston R., Kiff J., Sulston J., Kohara Y. Genome linking with yeast artificial chromosomes. Nature. 1988 Sep 8;335(6186):184–186. doi: 10.1038/335184a0. [DOI] [PubMed] [Google Scholar]
  12. 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]
  13. Davis M. W., Somerville D., Lee R. Y., Lockery S., Avery L., Fambrough D. M. Mutations in the Caenorhabditis elegans Na,K-ATPase alpha-subunit gene, eat-6, disrupt excitable cell function. J Neurosci. 1995 Dec;15(12):8408–8418. doi: 10.1523/JNEUROSCI.15-12-08408.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Eeckman F. H., Durbin R. ACeDB and macace. Methods Cell Biol. 1995;48:583–605. [PubMed] [Google Scholar]
  15. Ellis H. M., Horvitz H. R. Genetic control of programmed cell death in the nematode C. elegans. Cell. 1986 Mar 28;44(6):817–829. doi: 10.1016/0092-8674(86)90004-8. [DOI] [PubMed] [Google Scholar]
  16. Grabner M., Friedrich K., Knaus H. G., Striessnig J., Scheffauer F., Staudinger R., Koch W. J., Schwartz A., Glossmann H. Calcium channels from Cyprinus carpio skeletal muscle. Proc Natl Acad Sci U S A. 1991 Feb 1;88(3):727–731. doi: 10.1073/pnas.88.3.727. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Grabner M., Wang Z., Hering S., Striessnig J., Glossmann H. Transfer of 1,4-dihydropyridine sensitivity from L-type to class A (BI) calcium channels. Neuron. 1996 Jan;16(1):207–218. doi: 10.1016/s0896-6273(00)80037-9. [DOI] [PubMed] [Google Scholar]
  18. Hadley R. W., Lederer W. J. Ca2+ and voltage inactivate Ca2+ channels in guinea-pig ventricular myocytes through independent mechanisms. J Physiol. 1991 Dec;444:257–268. doi: 10.1113/jphysiol.1991.sp018876. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Hall D. H., Hedgecock E. M. Kinesin-related gene unc-104 is required for axonal transport of synaptic vesicles in C. elegans. Cell. 1991 May 31;65(5):837–847. doi: 10.1016/0092-8674(91)90391-b. [DOI] [PubMed] [Google Scholar]
  20. Hochner B., Klein M., Schacher S., Kandel E. R. Action-potential duration and the modulation of transmitter release from the sensory neurons of Aplysia in presynaptic facilitation and behavioral sensitization. Proc Natl Acad Sci U S A. 1986 Nov;83(21):8410–8414. doi: 10.1073/pnas.83.21.8410. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. 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]
  22. Huang L. S., Tzou P., Sternberg P. W. The lin-15 locus encodes two negative regulators of Caenorhabditis elegans vulval development. Mol Biol Cell. 1994 Apr;5(4):395–411. doi: 10.1091/mbc.5.4.395. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Huizinga J. D. Action potentials in gastrointestinal smooth muscle. Can J Physiol Pharmacol. 1991 Aug;69(8):1133–1142. doi: 10.1139/y91-166. [DOI] [PubMed] [Google Scholar]
  24. Mello C. C., Kramer J. M., Stinchcomb D., Ambros V. Efficient gene transfer in C.elegans: extrachromosomal maintenance and integration of transforming sequences. EMBO J. 1991 Dec;10(12):3959–3970. doi: 10.1002/j.1460-2075.1991.tb04966.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Mikami A., Imoto K., Tanabe T., Niidome T., Mori Y., Takeshima H., Narumiya S., Numa S. Primary structure and functional expression of the cardiac dihydropyridine-sensitive calcium channel. Nature. 1989 Jul 20;340(6230):230–233. doi: 10.1038/340230a0. [DOI] [PubMed] [Google Scholar]
  26. Mori Y., Friedrich T., Kim M. S., Mikami A., Nakai J., Ruth P., Bosse E., Hofmann F., Flockerzi V., Furuichi T. Primary structure and functional expression from complementary DNA of a brain calcium channel. Nature. 1991 Apr 4;350(6317):398–402. doi: 10.1038/350398a0. [DOI] [PubMed] [Google Scholar]
  27. Niidome T., Kim M. S., Friedrich T., Mori Y. Molecular cloning and characterization of a novel calcium channel from rabbit brain. FEBS Lett. 1992 Aug 10;308(1):7–13. doi: 10.1016/0014-5793(92)81038-n. [DOI] [PubMed] [Google Scholar]
  28. Raizen D. M., Avery L. Electrical activity and behavior in the pharynx of Caenorhabditis elegans. Neuron. 1994 Mar;12(3):483–495. doi: 10.1016/0896-6273(94)90207-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Schafer W. R., Kenyon C. J. A calcium-channel homologue required for adaptation to dopamine and serotonin in Caenorhabditis elegans. Nature. 1995 May 4;375(6526):73–78. doi: 10.1038/375073a0. [DOI] [PubMed] [Google Scholar]
  30. Schafer W. R., Sanchez B. M., Kenyon C. J. Genes affecting sensitivity to serotonin in Caenorhabditis elegans. Genetics. 1996 Jul;143(3):1219–1230. doi: 10.1093/genetics/143.3.1219. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Spencer A. N., Przysiezniak J., Acosta-Urquidi J., Basarsky T. A. Presynaptic spike broadening reduces junctional potential amplitude. Nature. 1989 Aug 24;340(6235):636–638. doi: 10.1038/340636a0. [DOI] [PubMed] [Google Scholar]
  32. Starich T. A., Lee R. Y., Panzarella C., Avery L., Shaw J. E. eat-5 and unc-7 represent a multigene family in Caenorhabditis elegans involved in cell-cell coupling. J Cell Biol. 1996 Jul;134(2):537–548. doi: 10.1083/jcb.134.2.537. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Trent C., Tsuing N., Horvitz H. R. Egg-laying defective mutants of the nematode Caenorhabditis elegans. Genetics. 1983 Aug;104(4):619–647. doi: 10.1093/genetics/104.4.619. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Wang Q., Shen J., Splawski I., Atkinson D., Li Z., Robinson J. L., Moss A. J., Towbin J. A., Keating M. T. SCN5A mutations associated with an inherited cardiac arrhythmia, long QT syndrome. Cell. 1995 Mar 10;80(5):805–811. doi: 10.1016/0092-8674(95)90359-3. [DOI] [PubMed] [Google Scholar]
  35. Wang S. Y., Wang G. K. A mutation in segment I-S6 alters slow inactivation of sodium channels. Biophys J. 1997 Apr;72(4):1633–1640. doi: 10.1016/S0006-3495(97)78809-X. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Warmke J. W., Ganetzky B. A family of potassium channel genes related to eag in Drosophila and mammals. Proc Natl Acad Sci U S A. 1994 Apr 12;91(8):3438–3442. doi: 10.1073/pnas.91.8.3438. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Williams B. D., Waterston R. H. Genes critical for muscle development and function in Caenorhabditis elegans identified through lethal mutations. J Cell Biol. 1994 Feb;124(4):475–490. doi: 10.1083/jcb.124.4.475. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Williams M. E., Brust P. F., Feldman D. H., Patthi S., Simerson S., Maroufi A., McCue A. F., Veliçelebi G., Ellis S. B., Harpold M. M. Structure and functional expression of an omega-conotoxin-sensitive human N-type calcium channel. Science. 1992 Jul 17;257(5068):389–395. doi: 10.1126/science.1321501. [DOI] [PubMed] [Google Scholar]
  39. Williams M. E., Feldman D. H., McCue A. F., Brenner R., Velicelebi G., Ellis S. B., Harpold M. M. Structure and functional expression of alpha 1, alpha 2, and beta subunits of a novel human neuronal calcium channel subtype. Neuron. 1992 Jan;8(1):71–84. doi: 10.1016/0896-6273(92)90109-q. [DOI] [PubMed] [Google Scholar]
  40. Wilson R., Ainscough R., Anderson K., Baynes C., Berks M., Bonfield J., Burton J., Connell M., Copsey T., Cooper J. 2.2 Mb of contiguous nucleotide sequence from chromosome III of C. elegans. Nature. 1994 Mar 3;368(6466):32–38. doi: 10.1038/368032a0. [DOI] [PubMed] [Google Scholar]
  41. Zhang J. F., Ellinor P. T., Aldrich R. W., Tsien R. W. Molecular determinants of voltage-dependent inactivation in calcium channels. Nature. 1994 Nov 3;372(6501):97–100. doi: 10.1038/372097a0. [DOI] [PubMed] [Google Scholar]
  42. Zhong Y., Wu C. F. Alteration of four identified K+ currents in Drosophila muscle by mutations in eag. Science. 1991 Jun 14;252(5012):1562–1564. doi: 10.1126/science.2047864. [DOI] [PubMed] [Google Scholar]
  43. de Leon M., Wang Y., Jones L., Perez-Reyes E., Wei X., Soong T. W., Snutch T. P., Yue D. T. Essential Ca(2+)-binding motif for Ca(2+)-sensitive inactivation of L-type Ca2+ channels. Science. 1995 Dec 1;270(5241):1502–1506. doi: 10.1126/science.270.5241.1502. [DOI] [PubMed] [Google Scholar]

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