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Fu Y, Shaw SA, Naami R, et al. Isoproterenol Promotes Rapid Ryanodine Receptor Movement to Bridging Integrator 1 (BIN1)-Organized Dyads. Circulation. 2016;133(4):388-97doi: 10.1161/CIRCULATIONAHA.115.018535.
Fu, Y., Shaw, S. A., Naami, R., Vuong, C. L., Basheer, W. A., Guo, X., & Hong, T. (2016). Isoproterenol Promotes Rapid Ryanodine Receptor Movement to Bridging Integrator 1 (BIN1)-Organized Dyads. Circulation, 133(4), 388-97. https://doi.org/10.1161/CIRCULATIONAHA.115.018535
Fu, Ying, et al. "Isoproterenol Promotes Rapid Ryanodine Receptor Movement to Bridging Integrator 1 (BIN1)-Organized Dyads." Circulation vol. 133,4 (2016): 388-97. doi: https://doi.org/10.1161/CIRCULATIONAHA.115.018535
Fu Y, Shaw SA, Naami R, Vuong CL, Basheer WA, Guo X, Hong T. Isoproterenol Promotes Rapid Ryanodine Receptor Movement to Bridging Integrator 1 (BIN1)-Organized Dyads. Circulation. 2016 Jan 26;133(4):388-97. doi: 10.1161/CIRCULATIONAHA.115.018535. Epub 2016 Jan 05. PMID: 26733606; PMCID: PMC4729615.
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Circulation. 2016 Jan 26;133(4):388-97. doi: 10.1161/CIRCULATIONAHA.115.018535. Epub 2016 Jan 05.

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

Circulation

Ying Fu, Seiji A Shaw, Robert Naami, Caresse L Vuong, Wassim A Basheer, Xiuqing Guo, TingTing Hong

Affiliations

  1. From Cedars-Sinai Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA (Y.F., S.A.S., R.N., C.L.V., W.A.B., T.H.); Institute for Translational Genomics and Population Sciences, Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA (X.G.); and Departments of Medicine, Cedars-Sinai Medical Center and UCLA, Los Angeles, CA (T.H.).
  2. From Cedars-Sinai Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA (Y.F., S.A.S., R.N., C.L.V., W.A.B., T.H.); Institute for Translational Genomics and Population Sciences, Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA (X.G.); and Departments of Medicine, Cedars-Sinai Medical Center and UCLA, Los Angeles, CA (T.H.). [email protected].

PMID: 26733606 PMCID: PMC4729615 DOI: 10.1161/CIRCULATIONAHA.115.018535

Abstract

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 CaV1.2 channels at t-tubules. Sympathetic tone regulates myocardial calcium transients through β-adrenergic receptor (β-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 CaV1.2 delivery, we explored whether β-AR-regulated RyRs are also affected by BIN1.

METHODS AND RESULTS: Isolated adult mouse hearts or cardiomyocytes were perfused for 5 minutes with the β-AR agonist isoproterenol (1 µmol/L) or the blockers CGP+ICI (baseline). Using biochemistry and superresolution fluorescent imaging, we identified that BIN1 clusters P-RyR and CaV1.2. Acute β-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 β-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.

© 2016 American Heart Association, Inc.

Keywords: BIN1 protein; heart failure; membrane microdomain; myocytes cardiac; receptors, adrenergic, beta; ryanodine receptor 2, mouse

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