Cardiac BIN1 folds T-tubule membrane, controlling ion flux and limiting arrhythmia.
Cardiac BIN1 folds T-tubule membrane, controlling ion flux and limiting arrhythmia.
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心肌细胞T-小管对调节离子流是重要的。桥接整合子1（BIN 1）是一种与钙通道运输相关的T-小管蛋白，在衰竭的心脏中下调。在这里，我们发现，心脏T-小管通常含有致密的保护内膜折叠，形成的心脏剪接异构体的BIN 1。在心脏Bin 1缺失的小鼠中，T-小管折叠减少，这不会改变整体心肌细胞形态，但会释放局部细胞外钙和钾离子的扩散，延长动作电位持续时间，并增加对室性心律失常的易感性。我们还发现，T-小管内折叠仅由BIN 1亚型BIN 1 +13+17拯救，其促进N-WASP依赖性肌动蛋白聚合以稳定心脏Z-盘处的T-小管膜。总之，BIN 1 +13+17招募肌动蛋白折叠T-小管膜，创造一个模糊的空间，保护性地限制离子通量。当BIN 1 +13+17降低时，如发生在获得性心肌病中，T-小管形态改变，可导致心律失常。
Cardiomyocyte T-tubules are important for regulating ionic flux. Bridging Integrator 1 (BIN1) is a T-tubule protein associated with calcium channel trafficking that is down-regulated in failing hearts. Here we find that cardiac T-tubules normally contain dense protective inner membrane folds that are formed by a cardiac spliced isoform of BIN1. In mice with cardiac Bin1 deletion, T-tubule folding is decreased which does not change overall cardiomyocyte morphology, but frees diffusion of local extracellular calcium and potassium ions, prolonging action potential duration, and increasing susceptibility to ventricular arrhythmias. We also find that T-tubule inner folds are rescued only by the BIN1 isoform BIN1+13+17, which promotes N-WASP dependent actin polymerization to stabilize T-tubule membrane at cardiac Z-discs. In conclusion, BIN1+13+17 recruits actin to fold T-tubule membrane, creating a fuzzy space that protectively restricts ionic flux. When BIN1+13+17 is decreased, as occurs in acquired cardiomyopathy, T-tubule morphology is altered and arrhythmias can result.
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