title: Deletion of the distal C terminus of CaV1.2 channels leads to loss of beta-adrenergic regulation and heart failure in vivo.
abstract: L-type calcium currents conducted by CaV1.2 channels initiate excitation-contraction coupling in cardiac and vascular smooth muscle. In the heart, the distal portion of the C terminus (DCT) is proteolytically processed in vivo and serves as a noncovalently associated autoinhibitor of CaV1.2 channel activity. This autoinhibitory complex, with A-kinase anchoring protein-15 (AKAP15) bound to the DCT, is hypothesized to serve as the substrate for β-adrenergic regulation in the fight-or-flight response. Mice expressing CaV1.2 channels with the distal C terminus deleted (DCT-/-) develop cardiac hypertrophy and die prematurely after E15. Cardiac hypertrophy and survival rate were improved by drug treatments that reduce peripheral vascular resistance and hypertension, consistent with the hypothesis that CaV1.2 hyperactivity in vascular smooth muscle causes hypertension, hypertrophy, and premature death. However, in contrast to expectation, L-type Ca2+ currents in cardiac myocytes from DCT-/- mice were dramatically reduced due to decreased cell-surface expression of CaV1.2 protein, and the voltage dependence of activation and the kinetics of inactivation were altered. CaV1.2 channels in DCT-/- myocytes fail to respond to activation of adenylyl cyclase by forskolin, and the localized expression of AKAP15 is reduced. Therefore, we conclude that the DCT of CaV1.2 channels is required in vivo for normal vascular regulation, cell-surface expression of CaV1.2 channels in cardiac myocytes, and β-adrenergic stimulation of L-type Ca2+ currents in the heart.
authors.affiliation: Department of Pharmacology, University of Washington, Seattle, Washington 98195-7280, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Fu
authors.forename: Ruth E
authors.initials: RE
authors.lastname: Westenbroek
authors.forename: Frank H
authors.initials: FH
authors.lastname: Yu
authors.forename: John P
authors.initials: JP
authors.lastname: Clark
authors.forename: Misty R
authors.initials: MR
authors.lastname: Marshall
authors.forename: Todd
authors.initials: T
authors.lastname: Scheuer
authors.forename: William A
authors.initials: WA
authors.lastname: Catterall
mesh_terms: D054758:A Kinase Anchor Proteins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D020746:Calcium Channels, L-Type / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism; D004594:Electrophysiology; D005260:Female; D005838:Genotype; D006333:Heart Failure / Q000235:genetics / Q000378:metabolism*; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D032383:Myocytes, Cardiac / Q000378:metabolism; D010641:Phenotype; D010766:Phosphorylation; D011247:Pregnancy; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D054758:A Kinase Anchor Proteins; C487791:Akap7 protein, mouse; C514350:CACNA1C protein, mouse; D020746:Calcium Channels, L-Type; D017868:Cyclic AMP-Dependent Protein Kinases