Abstract 17278: Deletion of Distal C-Terminus of Cav1.2 Channel Leads to Loss Of β-Adrenergic Regulation and Heart Failure in vivo
L-type calcium (Ca) currents conducted by CaV1.2 channels initiate excitation-contraction coupling in cardiac muscle. The C-terminus of CaV1.2 mediates a variety of interactions with intracellular regulators and second messengers. The distal portion of C-terminus (dCT) is proteolytically processed in vivo and serves as an autoinhibitory regulator by re-binding to the proximal C-terminus. This molecular complex is hypothesized to serve as the substrate for β-adrenergic regulation in the fight-or-flight response. The purpose of this study is to investigate the role of dCT in the regulation of CaV1.2 channel in vivo. Mice expressing the CaV1.2 channels in which the distal C-terminus has been truncated near the site of proteolytic processing (dCT−/−) demonstrate major developmental defects and die prematurely after E14. dCT−/− embryos have the hallmark features of congestive heart failure and develop cardiac hypertrophy as indicated by increased heart to body weight ratio (5.5 ± 0.2 vs. 4.2 ± 0.1 mg/g) compared to their wildtype (WT) littermate controls. Hypertrophy and survival rate of dCT−/− during E13 to E19 were improved by the Ca channel blocker isradipine and the angiotensin converting-enzyme inhibitor captopril administered maternally, consistent with countering the expected CaV1.2 hyperactivity due to loss of autoinhibition by dCT. However, in contrast to expectations, L-type Ca currents in dCT−/− myocytes are dramatically reduced due to reduced expression of CaV1.2 protein. In addition, the voltage dependence of activation and the kinetics of inactivation are altered in dCT−/− myocytes, and dCT−/− channels fail to respond to adenylyl cyclase activation by forskolin. Therefore, we conclude that in vivo physiological regulation of CaV1.2 channel expression, function, and regulation by β-adrenergic signaling pathway require the distal C-terminus as a component of the macromolecular complex containing the mature, proteolytically processed channel. These experiments support an essential role for dCT in Ca channel expression and regulation in vivo and reveal an unexpected role of this regulatory process in cardiac hypertrophy and heart failure.
- © 2010 by American Heart Association, Inc.