Rad regulation of Ca V 1.2 channels controls cardiac fight-or-flight response.

Autor: Papa A; Division of Cardiology, Department of Medicine, Columbia University, Vagelos College of Physicians and Surgeons, New York, NY, USA.; Department of Physiology and Cellular Biophysics, Columbia University, Vagelos College of Physicians and Surgeons, New York, NY, USA.; These authors contributed equally: Arianne Papa, Sergey I. Zakharov, Alexander N. Katchman, Jared S. Kushner., Zakharov SI; Division of Cardiology, Department of Medicine, Columbia University, Vagelos College of Physicians and Surgeons, New York, NY, USA.; These authors contributed equally: Arianne Papa, Sergey I. Zakharov, Alexander N. Katchman, Jared S. Kushner., Katchman AN; Division of Cardiology, Department of Medicine, Columbia University, Vagelos College of Physicians and Surgeons, New York, NY, USA.; These authors contributed equally: Arianne Papa, Sergey I. Zakharov, Alexander N. Katchman, Jared S. Kushner., Kushner JS; Division of Cardiology, Department of Medicine, Columbia University, Vagelos College of Physicians and Surgeons, New York, NY, USA.; These authors contributed equally: Arianne Papa, Sergey I. Zakharov, Alexander N. Katchman, Jared S. Kushner., Chen BX; Division of Cardiology, Department of Medicine, Columbia University, Vagelos College of Physicians and Surgeons, New York, NY, USA., Yang L; Division of Cardiology, Department of Medicine, Columbia University, Vagelos College of Physicians and Surgeons, New York, NY, USA., Liu G; Division of Cardiology, Department of Medicine, Columbia University, Vagelos College of Physicians and Surgeons, New York, NY, USA., Jimenez AS; Division of Cardiology, Department of Medicine, Columbia University, Vagelos College of Physicians and Surgeons, New York, NY, USA., Eisert RJ; Department of Systems Biology, Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, USA., Bradshaw GA; Department of Systems Biology, Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, USA., Dun W; Division of Cardiology, Department of Medicine, Columbia University, Vagelos College of Physicians and Surgeons, New York, NY, USA., Ali SR; Division of Cardiology, Department of Medicine, Columbia University, Vagelos College of Physicians and Surgeons, New York, NY, USA., Rodriques A; Division of Cardiology, Department of Medicine, Columbia University, Vagelos College of Physicians and Surgeons, New York, NY, USA., Zhou K; Division of Cardiology, Department of Medicine, Columbia University, Vagelos College of Physicians and Surgeons, New York, NY, USA., Topkara V; Division of Cardiology, Department of Medicine, Columbia University, Vagelos College of Physicians and Surgeons, New York, NY, USA., Yang M; Institute for Genomic Medicine, Columbia University, Vagelos College of Physicians and Surgeons, New York, NY, USA., Morrow JP; Division of Cardiology, Department of Medicine, Columbia University, Vagelos College of Physicians and Surgeons, New York, NY, USA., Tsai EJ; Division of Cardiology, Department of Medicine, Columbia University, Vagelos College of Physicians and Surgeons, New York, NY, USA., Karlin A; Department of Biochemistry and Molecular Biophysics, Vagelos College of Physicians and Surgeons, New York, NY, USA., Wan E; Division of Cardiology, Department of Medicine, Columbia University, Vagelos College of Physicians and Surgeons, New York, NY, USA., Kalocsay M; Department of Systems Biology, Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, USA.; Present address: Department of Experimental Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA., Pitt GS; Cardiovascular Research Institute and Department of Medicine, Weill Cornell Medical College, New York, NY, USA., Colecraft HM; Department of Physiology and Cellular Biophysics, Columbia University, Vagelos College of Physicians and Surgeons, New York, NY, USA.; Department of Pharmacology and Molecular Signaling, Columbia University, Vagelos College of Physicians and Surgeons, New York, NY, USA., Ben-Johny M; Department of Physiology and Cellular Biophysics, Columbia University, Vagelos College of Physicians and Surgeons, New York, NY, USA., Marx SO; Division of Cardiology, Department of Medicine, Columbia University, Vagelos College of Physicians and Surgeons, New York, NY, USA.; Department of Pharmacology and Molecular Signaling, Columbia University, Vagelos College of Physicians and Surgeons, New York, NY, USA.
Jazyk: angličtina
Zdroj: Nature cardiovascular research [Nat Cardiovasc Res] 2022 Nov; Vol. 1 (11), pp. 1022-1038. Date of Electronic Publication: 2022 Nov 14.
DOI: 10.1038/s44161-022-00157-y
Abstrakt: Fight-or-flight responses involve β-adrenergic-induced increases in heart rate and contractile force. In the present study, we uncover the primary mechanism underlying the heart's innate contractile reserve. We show that four protein kinase A (PKA)-phosphorylated residues in Rad, a calcium channel inhibitor, are crucial for controlling basal calcium current and essential for β-adrenergic augmentation of calcium influx in cardiomyocytes. Even with intact PKA signaling to other proteins modulating calcium handling, preventing adrenergic activation of calcium channels in Rad-phosphosite-mutant mice (4SA-Rad) has profound physiological effects: reduced heart rate with increased pauses, reduced basal contractility, near-complete attenuation of β-adrenergic contractile response and diminished exercise capacity. Conversely, expression of mutant calcium-channel β-subunits that cannot bind 4SA-Rad is sufficient to enhance basal calcium influx and contractility to adrenergically augmented levels of wild-type mice, rescuing the failing heart phenotype of 4SA-Rad mice. Hence, disruption of interactions between Rad and calcium channels constitutes the foundation toward next-generation therapeutics specifically enhancing cardiac contractility.
Competing Interests: Competing interests Columbia University, Harvard University and NY Presbyterian Hospital have filed a patent (WO/2021/003389), which is published and pending review, reporting a FRET-based method for screening small molecules that increase contractility for the treatment of heart failure. Inventors on this patent application are S.O.M., H.M.C., M.K., S.I.Z., A.N.K., M.B.J. and G.L. The FRET-based assay was utilized in this manuscript for assessing the effects of calyculin and whether 3DA-β2B and 2DA-β2B Ca2+ channel subunits bind to Rad.
Databáze: MEDLINE
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