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Nat Med. 2014 Jun;20(6):624-32. doi: 10.1038/nm.3543. Epub 2014 May 18.

Cardiac BIN1 folds T-tubule membrane, controlling ion flux and limiting arrhythmia.

Author information

1
1] Cedars-Sinai Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA. [2].
2
1] Department of Physiology, University of California San Francisco, San Francisco, California, USA. [2] Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, California, USA. [3].
3
Cedars-Sinai Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
4
Cardiovascular Research Institute, University of California San Francisco, San Francisco, California, USA.
5
Imperial Center for Translational and Experimental Medicine, Imperial College, London, UK.
6
Division of Cardiology, Department of Medicine, University of California San Francisco, San Francisco, California, USA.
7
1] Department of Physiology, University of California San Francisco, San Francisco, California, USA. [2] Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, California, USA. [3] Cardiovascular Research Institute, University of California San Francisco, San Francisco, California, USA. [4] Howard Hughes Medical Institute, San Francisco, California, USA.

Abstract

Cardiomyocyte T tubules are important for regulating ion flux. Bridging integrator 1 (BIN1) is a T-tubule protein associated with calcium channel trafficking that is downregulated in failing hearts. Here we find that cardiac T tubules normally contain dense protective inner membrane folds that are formed by a cardiac isoform of BIN1. In mice with cardiac Bin1 deletion, T-tubule folding is decreased, which does not change overall cardiomyocyte morphology but leads to free diffusion of local extracellular calcium and potassium ions, prolonging action-potential duration and increasing susceptibility to ventricular arrhythmias. We also found that T-tubule inner folds are rescued by expression of the BIN1 isoform BIN1+13+17, which promotes N-WASP-dependent actin polymerization to stabilize the T-tubule membrane at cardiac Z discs. BIN1+13+17 recruits actin to fold the T-tubule membrane, creating a 'fuzzy space' that protectively restricts ion flux. When the amount of the BIN1+13+17 isoform is decreased, as occurs in acquired cardiomyopathy, T-tubule morphology is altered, and arrhythmia can result.

PMID:
24836577
PMCID:
PMC4048325
DOI:
10.1038/nm.3543
[Indexed for MEDLINE]
Free PMC Article
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