A Mechanism of Calmodulin Modulation of the Human Cardiac Sodium Channel

被引：44

作者：

Johnson, Christopher N. ^{[1
,2
,4
,5
]}

Potet, Franck ^{[6
]}

Thompson, Matthew K. ^{[2
,4
]}

Kroncke, Brett M. ^{[1
,5
]}

Glazer, Andrew M. ^{[1
,5
]}

Voehler, Markus W. ^{[3
,4
]}

Knollmann, Bjorn C. ^{[1
,5
]}

George, Alfred L., Jr. ^{[6
]}

Chazin, Walter J. ^{[2
,3
,4
]}

机构：

[1] Vanderbilt Univ, Div Clin Pharmacol, Nashville, TN 37240 USA

[2] Vanderbilt Univ, Dept Biochem, Nashville, TN 37205 USA

[3] Vanderbilt Univ, Dept Chem, Box 1583, Nashville, TN 37235 USA

[4] Vanderbilt Univ, Ctr Struct Biol, Nashville, TN 37232 USA

[5] Vanderbilt Univ, Ctr Arrhythmia Res & Therapeut, Nashville, TN 37240 USA

[6] Northwestern Univ, Dept Pharmacol, Feinberg Sch Med, Chicago, IL 60611 USA

来源：

STRUCTURE | 2018年 / 26卷 / 05期

关键词：

SOLUTION NMR STRUCTURE; IQ MOTIF; EF-HAND; CALCIUM; INACTIVATION; DOMAIN; ARRHYTHMIA; PROTEINS; COMPLEX; NA;

D O I：

10.1016/j.str.2018.03.005

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

The function of the human cardiac sodium channel (Na(V)1.5) is modulated by the Ca2+ sensor calmodulin (CaM), but the underlying mechanism(s) are controversial and poorly defined. CaM has been reported to bind in a Ca2+-dependent manner to two sites in the intracellular loop that is critical for inactivation of NaV1.5 (inactivation gate [IG]). The affinity of CaM for the complete IG was significantly stronger than that of fragments that lacked both complete binding sites. Structural analysis by nuclear magnetic resonance, crystallographic, and scattering approaches revealed that CaM simultaneously engages both IG sites using an extended configuration. Patch-clamp recordings for wild-type and mutant channels with an impaired CaM-IG interaction revealed CaM binding to the IG promotes recovery from inactivation while impeding the kinetics of inactivation. Models of full-length NaV1.5 suggest that CaM binding to the IG directly modulates channel function by destabilizing the inactivated state, which would promote resetting of the IG after channels close.

引用

页码：683 / +

页数：15

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