Targeting cBIN1-microdomains for heart failure therapy development
Transverse-tubules (T-tubules) are membrane invaginations specific to striated muscles. Cardiac T-tubules are enriched with L-type calcium channels (LTCCs), which form dyads with ryanodine receptors (RyRs) to initiate intracellular calcium signaling critical for the beat-to-beat heart contraction. We previously identified that a membrane curvature protein, the cardiac isoform of BIN1 (Bridging Integrator 1) now called cBIN1, folds the membrane bilayer within T-tubules to control extracellular ion diffusion, protecting the hearts from arrhythmias (Figure 1). Over the years, we have identified that cBIN1-microdomains regulate myocardial function by facilitating microtubule-dependent LTCC delivery, clustering LTCCs and recruiting RyRs for effective dyad formation, and organizing SERCA2a for effective diastolic calcium removal and myocardial relaxation. In heart failure, disruption of cBIN1 microdomains causes impaired myocardial function, which can be normalized by cBin1 gene therapy. We are now further resolving the fundamental cell biology underlying cBIN1-microdomain formation, regulation, and turnover. The translational goal is to explore new strategies, via targeting cBIN1-microdomains, to develop novel therapies effective for patients with heart failure.