Regulation of the NaV1.5 cytoplasmic domain by calmodulin

被引：70

作者：

Gabelli, Sandra B. ^{[1
,2
,3
]}

Boto, Agedi ^{[1
]}

Kuhns, Victoria Halperin ^{[2
]}

Bianchet, Mario A. ^{[1
,4
]}

Farinelli, Federica ^{[2
]}

Aripirala, Srinivas ^{[1
]}

Yoder, Jesse ^{[1
]}

Jakoncic, Jean ^{[5
]}

Tomaselli, Gordon F. ^{[2
]}

Amzel, L. Mario ^{[1
]}

机构：

[1] Johns Hopkins Univ, Sch Med, Dept Biophys & Biophys Chem, Struct Enzymol & Thermodynam Grp, Baltimore, MD 21205 USA

[2] Johns Hopkins Univ, Sch Med, Dept Med, Div Cardiol, Baltimore, MD 21205 USA

[3] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21287 USA

[4] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21287 USA

[5] Brookhaven Natl Lab, Photon Sci Directorate, Natl Synchrotron Light Source, Upton, NY 11973 USA

来源：

NATURE COMMUNICATIONS | 2014年 / 5卷

关键词：

FACTOR HOMOLOGOUS FACTOR; SODIUM-CHANNEL NA(V)1.5; SOLUTION NMR STRUCTURE; C-TERMINAL DOMAIN; APO-CALMODULIN; EF-HAND; IQ MOTIF; MODULATION; CALCIUM; BINDING;

D O I：

10.1038/ncomms6126

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Voltage-gated sodium channels (Na-V) underlie the rapid upstroke of action potentials in excitable tissues. Binding of channel-interactive proteins is essential for controlling fast and long-term inactivation. In the structure of the complex of the carboxy-terminal portion of Na(V)1.5 (CTNa(V)1.5) with calmodulin (CaM)-Mg2+ reported here, both CaM lobes interact with the CTNa(V)1.5. On the basis of the differences between this structure and that of an inactivated complex, we propose that the structure reported here represents a non-inactivated state of the CTNaV, that is, the state that is poised for activation. Electrophysiological characterization of mutants further supports the importance of the interactions identified in the structure. Isothermal titration calorimetry experiments show that CaM binds to CTNa(V)1.5 with high affinity. The results of this study provide unique insights into the physiological activation and the pathophysiology of Na-V channels.

引用

页数：11

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