| First Author | Fu Y | Year | 2011 |
| Journal | J Biol Chem | Volume | 286 |
| Issue | 14 | Pages | 12617-26 |
| PubMed ID | 21216955 | Mgi Jnum | J:171162 |
| Mgi Id | MGI:4948808 | Doi | 10.1074/jbc.M110.175307 |
| Citation | Fu Y, et al. (2011) Deletion of the Distal C Terminus of CaV1.2 Channels Leads to Loss of {beta}-Adrenergic Regulation and Heart Failure in Vivo. J Biol Chem 286(14):12617-26 |
| abstractText | L-type calcium currents conducted by Ca(V)1.2 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 Ca(V)1.2 channel activity. This autoinhibitory complex, with A-kinase anchoring protein-15 (AKAP15) bound to the DCT, is hypothesized to serve as the substrate for beta-adrenergic regulation in the fight-or-flight response. Mice expressing Ca(V)1.2 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 Ca(V)1.2 hyperactivity in vascular smooth muscle causes hypertension, hypertrophy, and premature death. However, in contrast to expectation, L-type Ca(2+) currents in cardiac myocytes from DCT(-/-) mice were dramatically reduced due to decreased cell-surface expression of Ca(V)1.2 protein, and the voltage dependence of activation and the kinetics of inactivation were altered. Ca(V)1.2 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 Ca(V)1.2 channels is required in vivo for normal vascular regulation, cell-surface expression of Ca(V)1.2 channels in cardiac myocytes, and beta-adrenergic stimulation of L-type Ca(2+) currents in the heart. |
