Search tips
Search criteria 


Logo of jgenphysiolHomeThe Rockefeller University PressEditorsContactInstructions for AuthorsThis issue
J Gen Physiol. 1996 May 1; 107(5): 559–576.
PMCID: PMC2217015

Inactivation defects caused by myotonia-associated mutations in the sodium channel III-IV linker


Missense mutations in the skeletal muscle Na+ channel alpha subunit occur in several heritable forms of myotonia and periodic paralysis. Distinct phenotypes arise from mutations at two sites within the III-IV cytoplasmic loop: myotonia without weakness due to substitutions at glycine 1306, and myotonia plus weakness caused by a mutation at threonine 1313. Heterologous expression in HEK cells showed that substitutions at either site disrupted inactivation, as reflected by slower inactivation rates, shifts in steady-state inactivation, and larger persistent Na+ currents. For T1313M, however, the changes were an order of magnitude larger than any of three substitutions at G1306, and recovery from inactivation was hastened as well. Model simulations demonstrate that these functional difference have distinct phenotypic consequences. In particular, a large persistent Na+ current predisposes to paralysis due to depolarization-induced block of action potential generation.

Full Text

The Full Text of this article is available as a PDF (1.5M).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Aldrich RW, Stevens CF. Voltage-dependent gating of single sodium channels from mammalian neuroblastoma cells. J Neurosci. 1987 Feb;7(2):418–431. [PubMed]
  • Armstrong CM, Bezanilla F. Inactivation of the sodium channel. II. Gating current experiments. J Gen Physiol. 1977 Nov;70(5):567–590. [PMC free article] [PubMed]
  • Cannon SC, Corey DP. Loss of Na+ channel inactivation by anemone toxin (ATX II) mimics the myotonic state in hyperkalaemic periodic paralysis. J Physiol. 1993 Jul;466:501–520. [PubMed]
  • Cannon SC, Strittmatter SM. Functional expression of sodium channel mutations identified in families with periodic paralysis. Neuron. 1993 Feb;10(2):317–326. [PubMed]
  • Cannon SC, Brown RH, Jr, Corey DP. A sodium channel defect in hyperkalemic periodic paralysis: potassium-induced failure of inactivation. Neuron. 1991 Apr;6(4):619–626. [PubMed]
  • Cannon SC, Brown RH, Jr, Corey DP. Theoretical reconstruction of myotonia and paralysis caused by incomplete inactivation of sodium channels. Biophys J. 1993 Jul;65(1):270–288. [PubMed]
  • Cannon SC, Hayward LJ, Beech J, Brown RH., Jr Sodium channel inactivation is impaired in equine hyperkalemic periodic paralysis. J Neurophysiol. 1995 May;73(5):1892–1899. [PubMed]
  • Chahine M, George AL, Jr, Zhou M, Ji S, Sun W, Barchi RL, Horn R. Sodium channel mutations in paramyotonia congenita uncouple inactivation from activation. Neuron. 1994 Feb;12(2):281–294. [PubMed]
  • Cota G, Armstrong CM. Sodium channel gating in clonal pituitary cells. The inactivation step is not voltage dependent. J Gen Physiol. 1989 Aug;94(2):213–232. [PMC free article] [PubMed]
  • Deng WP, Nickoloff JA. Site-directed mutagenesis of virtually any plasmid by eliminating a unique site. Anal Biochem. 1992 Jan;200(1):81–88. [PubMed]
  • Heinemann SH, Conti F. Nonstationary noise analysis and application to patch clamp recordings. Methods Enzymol. 1992;207:131–148. [PubMed]
  • Ho SN, Hunt HD, Horton RM, Pullen JK, Pease LR. Site-directed mutagenesis by overlap extension using the polymerase chain reaction. Gene. 1989 Apr 15;77(1):51–59. [PubMed]
  • HODGKIN AL, HUXLEY AF. The dual effect of membrane potential on sodium conductance in the giant axon of Loligo. J Physiol. 1952 Apr;116(4):497–506. [PubMed]
  • Isom LL, De Jongh KS, Patton DE, Reber BF, Offord J, Charbonneau H, Walsh K, Goldin AL, Catterall WA. Primary structure and functional expression of the beta 1 subunit of the rat brain sodium channel. Science. 1992 May 8;256(5058):839–842. [PubMed]
  • Jackson CE, Barohn RJ, Ptacek LJ. Paramyotonia congenita: abnormal short exercise test, and improvement after mexiletine therapy. Muscle Nerve. 1994 Jul;17(7):763–768. [PubMed]
  • Jurman ME, Boland LM, Liu Y, Yellen G. Visual identification of individual transfected cells for electrophysiology using antibody-coated beads. Biotechniques. 1994 Nov;17(5):876–881. [PubMed]
  • Kraner SD, Tanaka JC, Barchi RL. Purification and functional reconstitution of the voltage-sensitive sodium channel from rabbit T-tubular membranes. J Biol Chem. 1985 May 25;260(10):6341–6347. [PubMed]
  • Kuo CC, Bean BP. Na+ channels must deactivate to recover from inactivation. Neuron. 1994 Apr;12(4):819–829. [PubMed]
  • Lerche H, Heine R, Pika U, George AL, Jr, Mitrovic N, Browatzki M, Weiss T, Rivet-Bastide M, Franke C, Lomonaco M, et al. Human sodium channel myotonia: slowed channel inactivation due to substitutions for a glycine within the III-IV linker. J Physiol. 1993 Oct;470:13–22. [PubMed]
  • McClatchey AI, Cannon SC, Slaugenhaupt SA, Gusella JF. The cloning and expression of a sodium channel beta 1-subunit cDNA from human brain. Hum Mol Genet. 1993 Jun;2(6):745–749. [PubMed]
  • Mitrović N, George AL, Jr, Heine R, Wagner S, Pika U, Hartlaub U, Zhou M, Lerche H, Fahlke C, Lehmann-Horn F. K(+)-aggravated myotonia: destabilization of the inactivated state of the human muscle Na+ channel by the V1589M mutation. J Physiol. 1994 Aug 1;478(Pt 3):395–402. [PubMed]
  • Mitrović N, George AL, Jr, Lerche H, Wagner S, Fahlke C, Lehmann-Horn F. Different effects on gating of three myotonia-causing mutations in the inactivation gate of the human muscle sodium channel. J Physiol. 1995 Aug 15;487(Pt 1):107–114. [PubMed]
  • O'Leary ME, Chen LQ, Kallen RG, Horn R. A molecular link between activation and inactivation of sodium channels. J Gen Physiol. 1995 Oct;106(4):641–658. [PMC free article] [PubMed]
  • Ricker K, Moxley RT, 3rd, Heine R, Lehmann-Horn F. Myotonia fluctuans. A third type of muscle sodium channel disease. Arch Neurol. 1994 Nov;51(11):1095–1102. [PubMed]
  • Riggs JE. The periodic paralyses. Neurol Clin. 1988 Aug;6(3):485–498. [PubMed]
  • Rüdel R, Lehmann-Horn F. Membrane changes in cells from myotonia patients. Physiol Rev. 1985 Apr;65(2):310–356. [PubMed]
  • Rüdel R, Ricker K, Lehmann-Horn F. Genotype-phenotype correlations in human skeletal muscle sodium channel diseases. Arch Neurol. 1993 Nov;50(11):1241–1248. [PubMed]
  • Sigworth FJ. The variance of sodium current fluctuations at the node of Ranvier. J Physiol. 1980 Oct;307:97–129. [PubMed]
  • Stühmer W, Conti F, Suzuki H, Wang XD, Noda M, Yahagi N, Kubo H, Numa S. Structural parts involved in activation and inactivation of the sodium channel. Nature. 1989 Jun 22;339(6226):597–603. [PubMed]
  • Tahmoush AJ, Schaller KL, Zhang P, Hyslop T, Heiman-Patterson T, Caldwell JH. Muscle sodium channel inactivation defect in paramyotonia congenita with the thr1313met mutation. Neuromuscul Disord. 1994 Sep-Nov;4(5-6):447–454. [PubMed]
  • Trimmer JS, Cooperman SS, Tomiko SA, Zhou JY, Crean SM, Boyle MB, Kallen RG, Sheng ZH, Barchi RL, Sigworth FJ, et al. Primary structure and functional expression of a mammalian skeletal muscle sodium channel. Neuron. 1989 Jul;3(1):33–49. [PubMed]
  • West JW, Patton DE, Scheuer T, Wang Y, Goldin AL, Catterall WA. A cluster of hydrophobic amino acid residues required for fast Na(+)-channel inactivation. Proc Natl Acad Sci U S A. 1992 Nov 15;89(22):10910–10914. [PubMed]
  • Yang N, Ji S, Zhou M, Ptácek LJ, Barchi RL, Horn R, George AL., 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. [PubMed]

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