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

Tingting Hong, Huanghe Yang, Shan Shan Zhang, Hee Cheol Cho, Mariya Kalashnikova, Baiming Sun, Hao Zhang, Anamika Bhargava, Michael Grabe, Jeffrey Olgin, Julia Gorelik, Eduardo Marbán, Lily Y. Jan, Robin M. Shaw

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)624-632
Number of pages9
JournalNature Medicine
Volume20
Issue number6
DOIs
StatePublished - 2014
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

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