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(Circulation Research. 2007;101:465.)
© 2007 American Heart Association, Inc.

Molecular Medicine

Protein Kinase G Phosphorylates Ca_v1.2 _1c and ß₂ Subunits

Lin Yang, Guoxia Liu, Sergey I. Zakharov, Andrew M. Bellinger, Marco Mongillo, Steven O. Marx

From the Division of Cardiology, Department of Medicine (L.Y., G.L., S.I.Z., S.O.M.), the Department of Pharmacology (S.O.M.), and the Wu Center for Molecular Cardiology (L.Y., G.L., S.I.Z., A.M.B., M.M., S.O.M.), Columbia University College of Physicians and Surgeons, New York.

Correspondence to Steven O. Marx, Department of Medicine, Division of Cardiology, Columbia University College of Physicians and Surgeons, 630 W 168th Street, P & S 9-401, New York, NY 10032. E-mail sm460{at}columbia.edu

Voltage-dependent Ca²⁺ channel function (Ca_v1.2, L-type Ca²⁺ channel) is required for cardiac excitation-contraction (E-C) coupling. Ca_v1.2 plays a key role in modulating cardiac function in response to classic signaling pathways, such as the renin-angiotensin system and sympathetic nervous system. Regulation of cardiac contraction by neurotransmitters and hormones is often correlated with Ca_v1.2 current through the actions of cAMP and cGMP. Cardiac cGMP, which activates protein kinase G (PKG), is regulated by nitric oxide (NO), and natriuretic peptides. Although PKG has been reported to activate or inhibit Ca_v1.2 function, it is still unclear whether Ca_v1.2 subunits are PKG substrates. We have identified phosphorylation sites within the _1c and ß_2a subunits that are phosphorylated by PKGI in vitro. We demonstrate that a subset of these phosphorylation sites is modulated, in a cGMP-PKG–specific manner, in intact HEK cells heterologously expressing _1c and ß_2a subunits. Using phospho-epitope–specific antibodies, we show that the phosphorylation of these residues is enhanced by PKG in intact cardiac myocytes. Activation of PKG in HEK cells transfected with _1c and ß_2a subunits caused an inhibition of Ca_v1.2 whole-cell current. PKG-mediated inhibition of Ca_v1.2 current was significantly reduced by coexpression of an alanine-substituted Ca_v1.2 ß_2a subunit (Ser⁴⁹⁶). Our results identify a molecular mechanism by which cGMP-PKG regulates Ca_v1.2 phosphorylation and function.

Key Words: Ca_v1.2 • calcium channel • protein kinase G • phosphorylation

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