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

Lawrence J. Hayward, Robert H. Brown, Stephen C. Cannon

Research output: Contribution to journalArticle

109 Citations (Scopus)

Abstract

Missense mutations in the skeletal muscle Na+ channel α 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 an 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 differences have distinct phenotypic consequences. In particular, a large persistent Na+ current predisposes to paralysis due to depolarization-induced block of action potential generation.

Original languageEnglish (US)
Pages (from-to)559-576
Number of pages18
JournalJournal of General Physiology
Volume107
Issue number5
DOIs
StatePublished - May 1996

Fingerprint

Myotonia
Sodium Channels
Paralysis
Mutation
Missense Mutation
Threonine
Glycine
Action Potentials
Skeletal Muscle
Phenotype

Keywords

  • familial
  • human
  • ion channels
  • muscle
  • paralysis

ASJC Scopus subject areas

  • Physiology

Cite this

Inactivation defects caused by myotonia-associated mutations in the sodium channel III-IV linker. / Hayward, Lawrence J.; Brown, Robert H.; Cannon, Stephen C.

In: Journal of General Physiology, Vol. 107, No. 5, 05.1996, p. 559-576.

Research output: Contribution to journalArticle

Hayward, Lawrence J. ; Brown, Robert H. ; Cannon, Stephen C. / Inactivation defects caused by myotonia-associated mutations in the sodium channel III-IV linker. In: Journal of General Physiology. 1996 ; Vol. 107, No. 5. pp. 559-576.
@article{402ccc7551954805b430a2414fef58bd,
title = "Inactivation defects caused by myotonia-associated mutations in the sodium channel III-IV linker",
abstract = "Missense mutations in the skeletal muscle Na+ channel α 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 an 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 differences have distinct phenotypic consequences. In particular, a large persistent Na+ current predisposes to paralysis due to depolarization-induced block of action potential generation.",
keywords = "familial, human, ion channels, muscle, paralysis",
author = "Hayward, {Lawrence J.} and Brown, {Robert H.} and Cannon, {Stephen C.}",
year = "1996",
month = "5",
doi = "10.1085/jgp.107.5.559",
language = "English (US)",
volume = "107",
pages = "559--576",
journal = "Journal of General Physiology",
issn = "0022-1295",
publisher = "Rockefeller University Press",
number = "5",

}

TY - JOUR

T1 - Inactivation defects caused by myotonia-associated mutations in the sodium channel III-IV linker

AU - Hayward, Lawrence J.

AU - Brown, Robert H.

AU - Cannon, Stephen C.

PY - 1996/5

Y1 - 1996/5

N2 - Missense mutations in the skeletal muscle Na+ channel α 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 an 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 differences have distinct phenotypic consequences. In particular, a large persistent Na+ current predisposes to paralysis due to depolarization-induced block of action potential generation.

AB - Missense mutations in the skeletal muscle Na+ channel α 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 an 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 differences have distinct phenotypic consequences. In particular, a large persistent Na+ current predisposes to paralysis due to depolarization-induced block of action potential generation.

KW - familial

KW - human

KW - ion channels

KW - muscle

KW - paralysis

UR - http://www.scopus.com/inward/record.url?scp=0029926886&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0029926886&partnerID=8YFLogxK

U2 - 10.1085/jgp.107.5.559

DO - 10.1085/jgp.107.5.559

M3 - Article

VL - 107

SP - 559

EP - 576

JO - Journal of General Physiology

JF - Journal of General Physiology

SN - 0022-1295

IS - 5

ER -