title: Cardiac BIN1 (cBIN1) is a regulator of cardiac contractile function and an emerging biomarker of heart muscle health.
abstract: In recent decades, a cardiomyocyte membrane scaffolding protein bridging integrator 1 (BIN1) has emerged as a critical multifunctional regulator of transverse-tubule (t-tubule) function and calcium signaling in cardiomyocytes. Encoded by a single gene with 20 exons that are alternatively spliced, more than ten BIN1 protein isoforms are expressed with tissue and disease specificity. The recently discovered cardiac alternatively spliced isoform BIN1 (cBIN1 or BIN1+13+17)plays a crucial role in organizing membrane microfolds within cardiac t-tubules. These cBIN1-induced microfolds form functional dyad microdomains by trafficking L-type calcium channels (LTCC) to t-tubule membrane and recruiting ryanodine receptors (RyR) to junctional sarcoplasmic reticulum membrane. When cBIN1 is transcriptionally reduced as occurs in heart failure, cBIN1-microfolds are disrupted and fail to form LTCC and RyR couplons. As a result, impaired dyad formation limits excitation-contraction coupling thus cardiac contractility, and accumulation of orphaned leaky RyRs outside of dyads increases ventricular arrhythmias. Reduced myocardial BIN1 in heart failure is also detectable at the blood level, and plasma BIN1 level predicts heart failure progression and future arrhythmias in cardiomyopathy patients. Here we will review the recent progress in BIN1-related cardiomyocyte biology studies and discuss the diagnostic and predictive values of cBIN1 in future clinical use.
authors.affiliation: Department of Cardiovascular Surgery, 2nd XiangYa Hospital, Central South University, Changsha, 410011, China.|Cedars-Sinai Heart Institute, Cedars-Sinai Medical Center, Los Angeles, 90048, USA.
authors.forename: Kang
authors.initials: K
authors.lastname: Zhou
authors.affiliation: Cedars-Sinai Heart Institute, Cedars-Sinai Medical Center, Los Angeles, 90048, USA. TingTing.Hong@cshs.org.|Departments of Medicine, Cedars-Sinai Medical Center and UCLA, Los Angeles, 90048, USA. TingTing.Hong@cshs.org.
authors.forename: Tingting
authors.initials: T
authors.lastname: Hong
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology*; D017398:Alternative Splicing; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000503:physiopathology; D020746:Calcium Channels, L-Type / Q000378:metabolism; D020013:Calcium Signaling; D006321:Heart / Q000502:physiology*; D006333:Heart Failure / Q000503:physiopathology; D006801:Humans; D008565:Membrane Proteins / Q000502:physiology; D051379:Mice; D009119:Muscle Contraction; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism; D009687:Nuclear Proteins / Q000502:physiology*; D020033:Protein Isoforms / Q000502:physiology; D019837:Ryanodine Receptor Calcium Release Channel / Q000502:physiology; D012519:Sarcoplasmic Reticulum / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C101410:BIN1 protein, human; D020746:Calcium Channels, L-Type; D008565:Membrane Proteins; D009687:Nuclear Proteins; D020033:Protein Isoforms; D019837:Ryanodine Receptor Calcium Release Channel; D025521:Tumor Suppressor Proteins
keywords: arrhythmias; cBIN1; calcium transient; heart failure; t-tubules