There goes the neighborhood: pathological alterations in T-tubule morphology and consequences for cardiomyocyte Ca2+ handling.

T-tubules are invaginations of the cardiomyocyte membrane into the cell interior which form a tortuous network. T-tubules provide proximity between the electrically excitable cell membrane and the sarcoplasmic reticulum, the main intracellular Ca2+ store. Tight coupling between the rapidly spreading action potential and Ca2+ release units in the SR membrane ensures synchronous Ca2+ release throughout the cardiomyocyte. This is a requirement for rapid and powerful contraction. In recent years, it has become clear that T-tubule structure and composition are altered in several pathological states which may importantly contribute to contractile defects in these conditions. In this review, we describe the "neighborhood" of proteins in the dyadic cleft which locally controls cardiomyocyte Ca2+ homeostasis and how alterations in T-tubule structure and composition may alter this neighborhood during heart failure, atrial fibrillation, and diabetic cardiomyopathy. Based on this evidence, we propose that T-tubules have the potential to serve as novel therapeutic targets.