Cardiac BIN1 folds T-tubule membrane, controlling ion flux and limiting arrhythmia.
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.
1] Cedars-Sinai Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA. [2].
TingTing
T
Hong
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].
Huanghe
H
Yang
Cedars-Sinai Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
Shan-Shan
SS
Zhang
Cedars-Sinai Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
Hee Cheol
HC
Cho
Cedars-Sinai Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
Mariya
M
Kalashnikova
Cedars-Sinai Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
Baiming
B
Sun
Cardiovascular Research Institute, University of California San Francisco, San Francisco, California, USA.
Hao
H
Zhang
Imperial Center for Translational and Experimental Medicine, Imperial College, London, UK.
Anamika
A
Bhargava
Cardiovascular Research Institute, University of California San Francisco, San Francisco, California, USA.
Michael
M
Grabe
Division of Cardiology, Department of Medicine, University of California San Francisco, San Francisco, California, USA.
Jeffrey
J
Olgin
Imperial Center for Translational and Experimental Medicine, Imperial College, London, UK.
Julia
J
Gorelik
Cedars-Sinai Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
Eduardo
E
Marbán
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.
Lily Y
LY
Jan
Cedars-Sinai Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
Robin M
RM
Shaw
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000378:metabolism*; D001483:Base Sequence; D002118:Calcium / Q000378:metabolism; D003001:Cloning, Molecular; D017931:DNA Primers / Q000235:genetics; D015342:DNA Probes / Q000235:genetics; D051379:Mice; D046529:Microscopy, Electron, Transmission; D008856:Microscopy, Fluorescence; D008969:Molecular Sequence Data; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000648:ultrastructure; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D012508:Sarcolemma / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; C109221:Bin1 protein, mouse; D017931:DNA Primers; D015342:DNA Probes; D009419:Nerve Tissue Proteins; D025521:Tumor Suppressor Proteins; D002118:Calcium