title: Ablation of HRC alleviates cardiac arrhythmia and improves abnormal Ca handling in CASQ2 knockout mice prone to CPVT.
abstract: Cardiac calsequestrin (CASQ2) and histidine-rich Ca-binding protein (HRC) are sarcoplasmic reticulum (SR) Ca-binding proteins that regulate SR Ca release in mammalian heart. Deletion of either CASQ2 or HRC results in relatively mild phenotypes characterized by preserved cardiac structure and function, although CASQ2 knockout (KO), or Cnull, shows increased arrhythmia burden under conditions of catecholaminergic stress. We hypothesized that given the apparent overlap of functions of CASQ2 and HRC, simultaneous ablation of both would deteriorate the cardiac phenotype compared with the single knockouts.
  
  
  
  In contrast to this expectation, double knockout (DKO) mice lacking both CASQ2 and HRC exhibited normal cardiac ejection fraction and ultrastructure. Moreover, the predisposition to catecholamine-dependent arrhythmia that characterizes the Cnull phenotype was alleviated in the DKO mice. At the myocyte level, DKO mice displayed Ca transients of normal amplitude; additionally, the frequency of spontaneous Ca waves and sparks in the presence of isoproterenol were decreased markedly compared with Cnull. Furthermore, restitution of SR Ca release was slowed in DKO myocytes compared with Cnull cells.
  
  
  
  Our results suggest that rather than being functionally redundant, CASQ2 and HRC modulate cardiac ryanodine receptor-mediated (RyR2) Ca release in an opposing manner. In particular, while CASQ2 stabilizes RyR2 rendering it refractory in the diastolic phase, HRC enhances RyR2 activity facilitating RyR2 recovery from refractoriness.
authors.affiliation: Department of Physiology and Cell Biology, College of Medicine, and Davis Heart and Lung Research Institute, The Ohio State University, 473 W. 12th Avenue, Columbus, OH 43210, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Liu
authors.affiliation: Department of Physiology and Cell Biology, College of Medicine, and Davis Heart and Lung Research Institute, The Ohio State University, 473 W. 12th Avenue, Columbus, OH 43210, USA.
authors.forename: Hsiang-Ting
authors.initials: HT
authors.lastname: Ho
authors.affiliation: Department of Physiology and Cell Biology, College of Medicine, and Davis Heart and Lung Research Institute, The Ohio State University, 473 W. 12th Avenue, Columbus, OH 43210, USA.
authors.forename: Lucia
authors.initials: L
authors.lastname: Brunello
authors.affiliation: Department of Physiology and Cell Biology, College of Medicine, and Davis Heart and Lung Research Institute, The Ohio State University, 473 W. 12th Avenue, Columbus, OH 43210, USA.
authors.forename: Sathya D
authors.initials: SD
authors.lastname: Unudurthi
authors.affiliation: Department of Physiology and Cell Biology, College of Medicine, and Davis Heart and Lung Research Institute, The Ohio State University, 473 W. 12th Avenue, Columbus, OH 43210, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Lou
authors.affiliation: Department of Physiology and Cell Biology, College of Medicine, and Davis Heart and Lung Research Institute, The Ohio State University, 473 W. 12th Avenue, Columbus, OH 43210, USA.
authors.forename: Andriy E
authors.initials: AE
authors.lastname: Belevych
authors.affiliation: Department of Physiology and Cell Biology, College of Medicine, and Davis Heart and Lung Research Institute, The Ohio State University, 473 W. 12th Avenue, Columbus, OH 43210, USA.
authors.forename: Lan
authors.initials: L
authors.lastname: Qian
authors.affiliation: School of Life Sciences and Systems Biology Research Center, Gwangju Institute of Science and Technology (GIST), Gwangju, Korea.
authors.forename: Do Han
authors.initials: DH
authors.lastname: Kim
authors.affiliation: School of Life Sciences and Systems Biology Research Center, Gwangju Institute of Science and Technology (GIST), Gwangju, Korea.
authors.forename: Chunghee
authors.initials: C
authors.lastname: Cho
authors.affiliation: Department of Physiology and Cell Biology, College of Medicine, and Davis Heart and Lung Research Institute, The Ohio State University, 473 W. 12th Avenue, Columbus, OH 43210, USA.
authors.forename: Paul M L
authors.initials: PM
authors.lastname: Janssen
authors.affiliation: Department of Physiology and Cell Biology, College of Medicine, and Davis Heart and Lung Research Institute, The Ohio State University, 473 W. 12th Avenue, Columbus, OH 43210, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Hund
authors.affiliation: Division of Clinical Pharmacology, Vanderbilt University Medical School, Nashville, TN 37232, USA.
authors.forename: Bjorn C
authors.initials: BC
authors.lastname: Knollmann
authors.affiliation: Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
authors.forename: Evangelia G
authors.initials: EG
authors.lastname: Kranias
authors.affiliation: Department of Physiology and Cell Biology, College of Medicine, and Davis Heart and Lung Research Institute, The Ohio State University, 473 W. 12th Avenue, Columbus, OH 43210, USA sandor.gyorke@osumc.edu.
authors.forename: Sándor
authors.initials: S
authors.lastname: Györke
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D002155:Calsequestrin / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D004452:Echocardiography; D007545:Isoproterenol; D018345:Mice, Knockout; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*; D017180:Tachycardia, Ventricular / Q000378:metabolism*; D000098850:Polymorphic Catecholaminergic Ventricular Tachycardia
chemical_list: D002135:Calcium-Binding Proteins; D002155:Calsequestrin; C489418:Hrc protein, mouse; D019837:Ryanodine Receptor Calcium Release Channel; C514388:casq2 protein, mouse; C000592748:ryanodine receptor 2. mouse; D007545:Isoproterenol; D002118:Calcium
keywords: Catecholaminergic polymorphic ventricular tachycardia; Excitation–contraction coupling; Ryanodine receptor