Adrenergic Ca V 1.2 Activation via Rad Phosphorylation Converges at α 1C I-II Loop.

Autor:	Papa A; Division of Cardiology, Department of Medicine (A.P., J.K., J.A.H., A.N.K., S.I.Z., B.-x.C., L.Y., R.L., S.L., G.L., D.R., X.L., V.T., S.O.M.), Columbia University, Vagelos College of Physicians and Surgeons, New York, NY.; Department of Physiology and Cellular Biophysics (A.P., J.D., P.J.d.R.M., H.M.C., O.C., M.B.-J.), Columbia University, Vagelos College of Physicians and Surgeons, New York, NY., Kushner J; Division of Cardiology, Department of Medicine (A.P., J.K., J.A.H., A.N.K., S.I.Z., B.-x.C., L.Y., R.L., S.L., G.L., D.R., X.L., V.T., S.O.M.), Columbia University, Vagelos College of Physicians and Surgeons, New York, NY., Hennessey JA; Division of Cardiology, Department of Medicine (A.P., J.K., J.A.H., A.N.K., S.I.Z., B.-x.C., L.Y., R.L., S.L., G.L., D.R., X.L., V.T., S.O.M.), Columbia University, Vagelos College of Physicians and Surgeons, New York, NY., Katchman AN; Division of Cardiology, Department of Medicine (A.P., J.K., J.A.H., A.N.K., S.I.Z., B.-x.C., L.Y., R.L., S.L., G.L., D.R., X.L., V.T., S.O.M.), Columbia University, Vagelos College of Physicians and Surgeons, New York, NY., Zakharov SI; Division of Cardiology, Department of Medicine (A.P., J.K., J.A.H., A.N.K., S.I.Z., B.-x.C., L.Y., R.L., S.L., G.L., D.R., X.L., V.T., S.O.M.), Columbia University, Vagelos College of Physicians and Surgeons, New York, NY., Chen BX; Division of Cardiology, Department of Medicine (A.P., J.K., J.A.H., A.N.K., S.I.Z., B.-x.C., L.Y., R.L., S.L., G.L., D.R., X.L., V.T., S.O.M.), Columbia University, Vagelos College of Physicians and Surgeons, New York, NY., Yang L; Division of Cardiology, Department of Medicine (A.P., J.K., J.A.H., A.N.K., S.I.Z., B.-x.C., L.Y., R.L., S.L., G.L., D.R., X.L., V.T., S.O.M.), Columbia University, Vagelos College of Physicians and Surgeons, New York, NY., Lu R; Division of Cardiology, Department of Medicine (A.P., J.K., J.A.H., A.N.K., S.I.Z., B.-x.C., L.Y., R.L., S.L., G.L., D.R., X.L., V.T., S.O.M.), Columbia University, Vagelos College of Physicians and Surgeons, New York, NY., Leong S; Division of Cardiology, Department of Medicine (A.P., J.K., J.A.H., A.N.K., S.I.Z., B.-x.C., L.Y., R.L., S.L., G.L., D.R., X.L., V.T., S.O.M.), Columbia University, Vagelos College of Physicians and Surgeons, New York, NY., Diaz J; Department of Physiology and Cellular Biophysics (A.P., J.D., P.J.d.R.M., H.M.C., O.C., M.B.-J.), Columbia University, Vagelos College of Physicians and Surgeons, New York, NY., Liu G; Division of Cardiology, Department of Medicine (A.P., J.K., J.A.H., A.N.K., S.I.Z., B.-x.C., L.Y., R.L., S.L., G.L., D.R., X.L., V.T., S.O.M.), Columbia University, Vagelos College of Physicians and Surgeons, New York, NY., Roybal D; Division of Cardiology, Department of Medicine (A.P., J.K., J.A.H., A.N.K., S.I.Z., B.-x.C., L.Y., R.L., S.L., G.L., D.R., X.L., V.T., S.O.M.), Columbia University, Vagelos College of Physicians and Surgeons, New York, NY.; Department of Pharmacology and Molecular Signaling (D.R., H.M.C., S.O.M.), Columbia University, Vagelos College of Physicians and Surgeons, New York, NY., Liao X; Division of Cardiology, Department of Medicine (A.P., J.K., J.A.H., A.N.K., S.I.Z., B.-x.C., L.Y., R.L., S.L., G.L., D.R., X.L., V.T., S.O.M.), Columbia University, Vagelos College of Physicians and Surgeons, New York, NY., Del Rivero Morfin PJ; Department of Physiology and Cellular Biophysics (A.P., J.D., P.J.d.R.M., H.M.C., O.C., M.B.-J.), Columbia University, Vagelos College of Physicians and Surgeons, New York, NY., Colecraft HM; Department of Physiology and Cellular Biophysics (A.P., J.D., P.J.d.R.M., H.M.C., O.C., M.B.-J.), Columbia University, Vagelos College of Physicians and Surgeons, New York, NY.; Department of Pharmacology and Molecular Signaling (D.R., H.M.C., S.O.M.), Columbia University, Vagelos College of Physicians and Surgeons, New York, NY., Pitt GS; Cardiovascular Research Institute, Weill Cornell Medical College, New York, New York (G.S.P.)., Clarke O; Department of Physiology and Cellular Biophysics (A.P., J.D., P.J.d.R.M., H.M.C., O.C., M.B.-J.), Columbia University, Vagelos College of Physicians and Surgeons, New York, NY., Topkara V; Division of Cardiology, Department of Medicine (A.P., J.K., J.A.H., A.N.K., S.I.Z., B.-x.C., L.Y., R.L., S.L., G.L., D.R., X.L., V.T., S.O.M.), Columbia University, Vagelos College of Physicians and Surgeons, New York, NY., Ben-Johny M; Department of Physiology and Cellular Biophysics (A.P., J.D., P.J.d.R.M., H.M.C., O.C., M.B.-J.), Columbia University, Vagelos College of Physicians and Surgeons, New York, NY., Marx SO; Division of Cardiology, Department of Medicine (A.P., J.K., J.A.H., A.N.K., S.I.Z., B.-x.C., L.Y., R.L., S.L., G.L., D.R., X.L., V.T., S.O.M.), Columbia University, Vagelos College of Physicians and Surgeons, New York, NY.; Department of Pharmacology and Molecular Signaling (D.R., H.M.C., S.O.M.), Columbia University, Vagelos College of Physicians and Surgeons, New York, NY.
Jazyk:	angličtina
Zdroj:	Circulation research [Circ Res] 2021 Jan 08; Vol. 128 (1), pp. 76-88. Date of Electronic Publication: 2020 Oct 22.
DOI:	10.1161/CIRCRESAHA.120.317839
Abstrakt:	Rationale: Changing activity of cardiac Ca V 1.2 channels under basal conditions, during sympathetic activation, and in heart failure is a major determinant of cardiac physiology and pathophysiology. Although cardiac Ca V 1.2 channels are prominently upregulated via activation of PKA (protein kinase A), essential molecular details remained stubbornly enigmatic. Objective: The primary goal of this study was to determine how various factors converging at the Ca V 1.2 I-II loop interact to regulate channel activity under basal conditions, during β-adrenergic stimulation, and in heart failure. Methods and Results: We generated transgenic mice with expression of Ca V 1.2 α 1C subunits with (1) mutations ablating interaction between α 1C and β-subunits, (2) flexibility-inducing polyglycine substitutions in the I-II loop (GGG-α 1C ), or (3) introduction of the alternatively spliced 25-amino acid exon 9* mimicking a splice variant of α 1C upregulated in the hypertrophied heart. Introducing 3 glycine residues that disrupt a rigid IS6-α-interaction domain helix markedly reduced basal open probability despite intact binding of Ca V β to α 1C I-II loop and eliminated β-adrenergic agonist stimulation of Ca V 1.2 current. In contrast, introduction of the exon 9* splice variant in the α 1C I-II loop, which is increased in ventricles of patients with end-stage heart failure, increased basal open probability but did not attenuate stimulatory response to β-adrenergic agonists when reconstituted heterologously with β 2B and Rad or transgenically expressed in cardiomyocytes. Conclusions: Ca 2+ channel activity is dynamically modulated under basal conditions, during β-adrenergic stimulation, and in heart failure by mechanisms converging at the α 1C I-II loop. Ca V β binding to α 1C stabilizes an increased channel open probability gating mode by a mechanism that requires an intact rigid linker between the β-subunit binding site in the I-II loop and the channel pore. Release of Rad-mediated inhibition of Ca 2+ channel activity by β-adrenergic agonists/PKA also requires this rigid linker and β-binding to α 1C .
Databáze:	MEDLINE
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