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

被引:110
作者
Hayward, LJ
Brown, RH
Cannon, SC
机构
[1] MASSACHUSETTS GEN HOSP,DEPT NEUROL,BOSTON,MA 02114
[2] HARVARD UNIV,SCH MED,DEPT NEUROBIOL,BOSTON,MA 02115
关键词
muscle; paralysis; familial; ion channels; human;
D O I
10.1085/jgp.107.5.559
中图分类号
Q4 [生理学];
学科分类号
071003 ;
摘要
Missense mutations in the skeletal muscle Na+ channel a 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 a persistent Na+ currents. For Tl313M, 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.
引用
收藏
页码:559 / 576
页数:18
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