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

Nature Medicine volume 20, pages 624–632 (2014)Cite this article

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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.

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Figure 1: Cardiomyocyte T tubules are densely folded by BIN1.
Figure 2: Bin1 deletion increases extracellular Ca2+ diffusion.
Figure 3: Bin1 deletion increases extracellular K+ diffusion, prolonging action-potential duration and increasing ventricular ectopy.
Figure 4: Ventricular arrhythmias induced by pacing and β adrenergic activation with isoproterenol.
Figure 5: Adult mouse cardiomyocytes express four Bin1 splice variants.
Figure 6: BIN1+13+17 uses F-actin to connect to Z-disc α-actinin.

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Acknowledgements

This work was supported by US National Institutes of Health grants R01 HL094414 (R.M.S.), R37 MH065334 (L.Y.J.), WT090594 (J.G.), R21 GM100224 (M.G.), T32 HL116273 (S.-S.Z.) and K99/R00 HL109075 (T.H.) and by the American Heart Association (S.-S.Z. and R.M.S.). L.Y.J. is a Howard Hughes Medical Institute investigator. We thank E. Cingolani for helpful advice on designing the in vivo pacing protocol, D. Laury-Kleintop and G.C. Prendergast from the Lankenau Institute for Medical Research for Bin1-loxP mice, J. Mulholland and J.J. Perrino for TEM imaging at the Electron Microscopy Core of the Cell Sciences Imaging Facility at the Stanford University Medical Center, J. Smyth and R. Wirka for helpful discussions and T.S. Fong and T. Hitzeman for technical assistance.

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Author notes

  1. TingTing Hong and Huanghe Yang: These authors contributed equally to this work.

Authors and Affiliations

  1. Cedars-Sinai Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA

    TingTing Hong, Shan-Shan Zhang, Hee Cheol Cho, Mariya Kalashnikova, Baiming Sun, Eduardo Marbán & Robin M Shaw

  2. Department of Physiology, University of California San Francisco, San Francisco, California, USA

    Huanghe Yang & Lily Y Jan

  3. Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, California, USA

    Huanghe Yang & Lily Y Jan

  4. Cardiovascular Research Institute, University of California San Francisco, San Francisco, California, USA

    Hao Zhang, Michael Grabe & Lily Y Jan

  5. Imperial Center for Translational and Experimental Medicine, Imperial College, London, UK

    Anamika Bhargava & Julia Gorelik

  6. Division of Cardiology, Department of Medicine, University of California San Francisco, San Francisco, California, USA

    Jeffrey Olgin

  7. Howard Hughes Medical Institute, San Francisco, California, USA

    Lily Y Jan

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Contributions

All authors contributed to study design, analysis of the data and writing of the paper. T.H. was involved in the design and performance of all key experiments. H.Y. did the patch-clamp experiments. S.-S.Z. prepared mouse crossing, adenovirus and Bin1 cloning experiments. H.C.C. and B.S. did the in vivo arrhythmia experiments. M.K. performed the actin polymerization assay. A.B. did the scanning ion-conductance microscopy imaging and analysis of T-tubule topology. H.Z. did the optical mapping studies. M.G. did the mathematical modeling.

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Correspondence to Robin M Shaw.

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Hong, T., Yang, H., Zhang, SS. et al. Cardiac BIN1 folds T-tubule membrane, controlling ion flux and limiting arrhythmia. Nat Med 20, 624–632 (2014). https://doi.org/10.1038/nm.3543

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