title: CAPON modulates cardiac repolarization via neuronal nitric oxide synthase signaling in the heart.
abstract: Congenital long- or short-QT syndrome may lead to life-threatening ventricular tachycardia and sudden cardiac death. Apart from the rare disease-causing mutations, common genetic variants in CAPON, a neuronal nitric oxide synthase (NOS1) regulator, have recently been associated with QT interval variations in a human whole-genome association study. CAPON had been unsuspected of playing a role in cardiac repolarization; indeed, its physiological role in the heart (if any) is unknown. To define the biological effects of CAPON in the heart, we investigated endogenous CAPON protein expression and protein-protein interactions in the heart and performed electrophysiological studies in isolated ventricular myocytes with and without CAPON overexpression. We find that CAPON protein is expressed in the heart and interacts with NOS1 to accelerate cardiac repolarization by inhibition of L-type calcium channel. Our findings provide a rationale for the association of CAPON gene variants with extremes of the QT interval in human populations.
authors.affiliation: Institute of Molecular Cardiobiology, The Johns Hopkins University, Baltimore, MD 21205, USA.
authors.forename: Kuan-Cheng
authors.initials: KC
authors.lastname: Chang
authors.forename: Andreas S
authors.initials: AS
authors.lastname: Barth
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Sasano
authors.forename: Eddy
authors.initials: E
authors.lastname: Kizana
authors.forename: Yuji
authors.initials: Y
authors.lastname: Kashiwakura
authors.forename: Yiqiang
authors.initials: Y
authors.lastname: Zhang
authors.forename: D Brian
authors.initials: DB
authors.lastname: Foster
authors.forename: Eduardo
authors.initials: E
authors.lastname: Marbán
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D020747:Calcium Channels, T-Type / Q000378:metabolism; D002460:Cell Line; D016764:Cell Polarity; D004594:Electrophysiology; D005786:Gene Expression Regulation; D006168:Guinea Pigs; D006801:Humans; D009206:Myocardium / Q000166:cytology* / Q000378:metabolism*; D009569:Nitric Oxide / Q000096:biosynthesis; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D011188:Potassium / Q000378:metabolism; D011485:Protein Binding; D015398:Signal Transduction; D012964:Sodium / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D020747:Calcium Channels, T-Type; D009569:Nitric Oxide; D012964:Sodium; D052248:Nitric Oxide Synthase Type I; D011188:Potassium