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

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Hong, T; Yang, H; Zhang, S-S; Cho, HC; Kalashnikova, M; Sun, B; Zhang, H; Bhargava, A; Grabe, M; Olgin, J; Gorelik, J; Marbán, E; Jan, LY; Shaw, RM

Published Date

  • June 2014

Published In

Volume / Issue

  • 20 / 6

Start / End Page

  • 624 - 632

PubMed ID

  • 24836577

Pubmed Central ID

  • 24836577

Electronic International Standard Serial Number (EISSN)

  • 1546-170X

Digital Object Identifier (DOI)

  • 10.1038/nm.3543

Language

  • eng

Conference Location

  • United States