Function of BIN1-Induced T-Tubule Microdomains
T-tubules are membrane invaginations specific to striated muscles. Cardiac T-tubules (TT) are enriched with L-type calcium channels (LTCCs), which initiate intracellular calcium signaling that is critical for beat-to-beat contraction. The Hong Laboratory recently identified that a membrane curvature protein, cardiac BIN1 (cBIN1, Bridging Integrator 1), folds the membrane bilayer within T-tubules to control extracellular ion diffusion, protecting the hearts from arrhythmias (Figure 1). More recently, we identified that cBIN1-microfolds are organizing the cardiomyocyte LTCC-RyR dyads, responsible for efficient excitation-contraction coupling in the heart. We previously identified that BIN1 facilitates microtubule-dependent delivery of LTCCs to T-tubules, and expression of BIN1 is reduced in human heart failure, resulting in intracellular accumulation of LTCCs. We are further learning how these BIN1 folded microdomains regulate LTCC-RyR couplon formation and function in normal and failing cardiomyocytes.
Turnover of Membrane Microdomains and Release of Biomarkers
During heart failure, T-tubules not only undergo membrane remodeling, but also lose their membrane LTCCs, causing impaired calcium transients and decreased contractility. We also found that T-tubule membrane associated BIN1 is reduced in human heart failure, diminishing cardiac contractility. Furthermore, BIN1 is blood available, and plasma BIN1 decreases during heart failure progression. We are very interested in how these BIN1-dependent cardiac T-tubule microdomains are turned over, releasing membrane and associated BIN1 into blood. The released BIN1, with direct relevance to cardiomyocyte health and recovery potential, is a potential biomarker of heart failure.