Isoproterenol Promotes Rapid Ryanodine Receptor Movement to Bridging Integrator 1 (BIN1)-Organized Dyads

Article

关键词: CALCIUM-RELEASE CHANNELS;    HEART-FAILURE;    CA2+ CHANNELS;    SARCOPLASMIC-RETICULUM;    RYR2 PHOSPHORYLATION;    PKA PHOSPHORYLATION;    TRANSVERSE TUBULES;    KINASE-II;    BIN1;    MUSCLE;   

DOI  :  10.1161/CIRCULATIONAHA.115.018535

来源: SCIE

【 摘 要 】

Background The key pathophysiology of human acquired heart failure is impaired calcium transient, which is initiated at dyads consisting of ryanodine receptors (RyRs) at sarcoplasmic reticulum apposing Ca(V)1.2 channels at t-tubules. Sympathetic tone regulates myocardial calcium transients through -adrenergic receptor (-AR)-mediated phosphorylation of dyadic proteins. Phosphorylated RyRs (P-RyR) have increased calcium sensitivity and open probability, amplifying calcium transient at a cost of receptor instability. Given that bridging integrator 1 (BIN1) organizes t-tubule microfolds and facilitates Ca(V)1.2 delivery, we explored whether -AR-regulated RyRs are also affected by BIN1. Methods and Results Isolated adult mouse hearts or cardiomyocytes were perfused for 5 minutes with the -AR agonist isoproterenol (1 mu mol/L) or the blockers CGP+ICI (baseline). Using biochemistry and superresolution fluorescent imaging, we identified that BIN1 clusters P-RyR and Ca(V)1.2. Acute -AR activation increases coimmunoprecipitation between P-RyR and cardiac spliced BIN1+13+17 (with exons 13 and 17). Isoproterenol redistributes BIN1 to t-tubules, recruiting P-RyRs and improving the calcium transient. In cardiac-specific Bin1 heterozygote mice, isoproterenol fails to concentrate BIN1 to t-tubules, impairing P-RyR recruitment. The resultant accumulation of uncoupled P-RyRs increases the incidence of spontaneous calcium release. In human hearts with end-stage ischemic cardiomyopathy, we find that BIN1 is also 50% reduced, with diminished P-RyR association with BIN1. Conclusions On -AR activation, reorganization of BIN1-induced microdomains recruits P-RyR into dyads, increasing the calcium transient while preserving electric stability. When BIN1 is reduced as in human acquired heart failure, acute stress impairs microdomain formation, limiting contractility and promoting arrhythmias.

【 授权许可】

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