Crystallographic basis for calcium regulation of sodium channels

Maen F Sarhan; Ching-Chieh Tung; Filip Van Petegem; Christopher A Ahern

doi:10.1073/pnas.1114748109

Back

Crystallographic basis for calcium regulation of sodium channels

Journal article

Open access

Peer reviewed

Crystallographic basis for calcium regulation of sodium channels

Maen F Sarhan, Ching-Chieh Tung, Filip Van Petegem and Christopher A Ahern

Proceedings of the National Academy of Sciences - PNAS, Vol.109(9), pp.3558-3563

02/28/2012

DOI: 10.1073/pnas.1114748109

PMCID: PMC3295267

PMID: 22331908

Files and links (1)

url

https://doi.org/10.1073/pnas.1114748109View

Published (Version of record) Open Access

Abstract

Voltage-gated sodium channels underlie the rapid regenerative upstroke of action potentials and are modulated by cytoplasmic calcium ions through a poorly understood mechanism. We describe the 1.35 Å crystal structure of Ca 2+ -bound calmodulin (Ca 2+ /CaM) in complex with the inactivation gate (DIII-IV linker) of the cardiac sodium channel (Na V 1.5). The complex harbors the positions of five disease mutations involved with long Q-T type 3 and Brugada syndromes. In conjunction with isothermal titration calorimetry, we identify unique inactivation-gate mutations that enhance or diminish Ca 2+ /CaM binding, which, in turn, sensitize or abolish Ca 2+ regulation of full-length channels in electrophysiological experiments. Additional biochemical experiments support a model whereby a single Ca 2+ /CaM bridges the C-terminal IQ motif to the DIII-IV linker via individual N and C lobes, respectively. The data suggest that Ca 2+ /CaM destabilizes binding of the inactivation gate to its receptor, thus biasing inactivation toward more depolarized potentials.

Biological Sciences

patch-clamp electrophysiology

crystallography

structural biology

cardiac arrhythmia

Details

Title: Subtitle: Crystallographic basis for calcium regulation of sodium channels
Creators: Maen F Sarhan - Departments of
Ching-Chieh Tung - Biochemistry and Molecular Biology, Life Sciences Institute
Filip Van Petegem - Biochemistry and Molecular Biology, Life Sciences Institute
Christopher A Ahern - Departments of
Resource Type: Journal article
Publication Details: Proceedings of the National Academy of Sciences - PNAS, Vol.109(9), pp.3558-3563
DOI: 10.1073/pnas.1114748109
PMID: 22331908
PMCID: PMC3295267
NLM abbreviation: Proc Natl Acad Sci U S A
ISSN: 0027-8424
eISSN: 1091-6490
Publisher: National Academy of Sciences
Language: English
Date published: 02/28/2012
Academic Unit: Molecular Physiology and Biophysics; Iowa Neuroscience Institute
Record Identifier: 9984070702302771

Metrics

10 Record Views

116 Times Cited - Web of Science