Cardiac BIN1 folds T-tubule membrane, controlling ion flux and limiting arrhythmia.
Journal Article (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
- PMC4048325
Electronic International Standard Serial Number (EISSN)
- 1546-170X
Digital Object Identifier (DOI)
- 10.1038/nm.3543
Language
- eng
Conference Location
- United States