Published online before print July 12, 2007, doi: 10.1161/CIRCRESAHA.107.156976
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Submitted on January 24, 2007
Revised on May 31, 2007
Accepted on June 28, 2007
Protein Kinase G Phosphorylates Cav1.2 
1c and 
2 Subunits
Lin Yang ;
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.
* To whom correspondence should be addressed. E-mail: sm460{at}columbia.edu.
Voltage-dependent Ca2+ channel function (Cav1.2, L-type Ca2+ channel) is required for cardiac excitation-contraction (E-C) coupling. Cav1.2 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 Cav1.2 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 Cav1.2 function, it is still unclear whether Cav1.2 subunits are PKG substrates. We have identified phosphorylation sites within the 
1c and 
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 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 2a subunits caused an inhibition of Cav1.2 whole-cell current. PKG-mediated inhibition of Cav1.2 current was significantly reduced by coexpression of an alanine-substituted Cav1.2 2a subunit (Ser496). Our results identify a molecular mechanism by which cGMP-PKG regulates Cav1.2 phosphorylation and function.
Key words: Cav1.2 • calcium channel • protein kinase G • phosphorylation
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