Abstract 18517: Cardiac BIN1 Folds T-Tubule Membrane to Control Ion Flux and Limit Arrhythmia

Abstract

Cardiomyocyte T-tubules allow electrical stimuli to quickly reach the cell interior, triggering calcium transients and muscle contraction. Bridging Integrator 1 (BIN1), a membrane scaffolding protein associated with calcium channel trafficking to cardiac T-tubules, is down-regulated in failing hearts. Here we find that BIN1 also mediates dense folding within cardiac T-tubule invaginations. In mice, heterozygous cardiac specific Bin1 deletion does not affect cardiomyocyte morphology, but on microscopy (Figure 1) and electrophysiological studies, BIN1 knockout removes the T-tubule folds, increasing the rate of local extracellular calcium and potassium ion diffusion. Loss of folds also results in prolongation in cardiomyocyte action potential duration and spontaneous ventricular ectopy in intact animals. We find that the T-tubule folds are rescued by a particular BIN1 isoform, BIN1+13+17, which is specific for cardiac T-tubules, and non-existent in skeletal muscle. We found that BIN1+13+17 uses actin to stabilize cardiac T-tubule membrane at Z-discs, explaining how the folds can form. In conclusion, a cardiac BIN1 isoform recruits the actin cytoskeleton to fold T-tubule membrane, creating a fuzzy space that regulates ion flux and protects against arrhythmia. When BIN1 is decreased, such as in heart failure, arrhythmias can result. Figure 1: TEM images at 150,000X magnification of individual T-tubule cross sections in WT and BIN1 HT mice. Note extra membrane in the WT T-tubule. Bottom panel contains intensity profiles of the two images.