Novel LQT-3 mutation affects Na+ channel activity through interactions between α- and β1-subunits

被引:154
作者
An, RH
Wang, XL
Kerem, B
Benhorin, J
Medina, A
Goldmit, M
Kass, RS
机构
[1] Columbia Univ Coll Phys & Surg, Dept Pharmacol, New York, NY 10032 USA
[2] Hebrew Univ Jerusalem, Dept Genet, IL-91904 Jerusalem, Israel
[3] Bikur Cholim Hosp, Heiden Dept Cardiol, IL-91904 Jerusalem, Israel
关键词
long-QT syndrome; genetics; Na+ channel;
D O I
10.1161/01.RES.83.2.141
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
The congenital long-QT syndrome (LQT), an inherited cardiac arrhythmia characterized in part by prolonged ventricular repolarization, has been linked to 5 loci, 4 of which have been shown to harbor genes that encode ion channels. Previously studied LQT-3 mutations of SCN5A (or hH1), the gene that encodes the human Na+ channel alpha-subunit, have been shown to encode voltage-gated Na+ channels that reopen during prolonged depolarization and hence directly contribute to the disease phenotype: delayed repolarization. Here, we report the functional consequences of a novel SCN5A mutation discovered in an extended LQT family, The mutation, a single A-->G base substitution at nucleotide 5519 of the SCN5A cDNA, is expected to cause a nonconservative change from an aspartate to a glycine at position 1790 (D1790G) of the SCN5A gene product. We investigated ion channel activity in human embryonic kidney (HEK 293) cells transiently transfected with wild-type (hH1) or mutant (D1790G) cDNA alone or in combination with cDNA encoding the human Na+ channel beta(1)-subunit (h beta(1)) using whole-cell patch-clamp procedures. Heteromeric channels formed by coexpression of alpha- and beta(1)-subunits are affected: steady-state inactivation is shifted by -16 mV, but there is no D1790G-induced sustained inward current. This effect is independent of the beta(1)-subunit isoform. We find no significant effect of D1790G on the biophysical properties of monomeric alpha- (hH1) channels. We conclude that the effects of the novel LQT-3 mutation on inactivation of heteromeric channels are due to D1790G-induced changes in alpha- and beta(1)-interactions.
引用
收藏
页码:141 / 146
页数:6
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