Ser1928 is a common site for Cav1.2 phosphorylation by protein kinase C isoforms.
Voltage-dependent Ca(2+) channel (Ca(v)1.2, L-type Ca(2+) channel) function is highly regulated by hormones and neurotransmitters in large part through the activation of kinases and phosphatases. Regulation of Ca(v)1.2 by protein kinase C (PKC) is of significant physiologic importance, mediating, in part, the cardiac response to hormonal regulation. Although PKC has been reported to mediate activation and/or inhibition of Ca(v)1.2 function, the molecular mechanisms mediating the response have not been definitively elucidated. We show that PKC forms a macromolecular complex with the alpha(1c) subunit of Ca(v)1.2 through direct interaction with the C terminus. This interaction leads to phosphorylation of the channel in response to activators of PKC. We identify Ser(1928) as the residue that is phosphorylated by PKC in vitro and in vivo. Ser(1928) has been identified previously as the site mediating, in part, the protein kinase A up-regulation of channel activity. Thus, the protein kinase A and PKC signaling pathways converge on the Ca(v)1.2 complex at Ser(1928) to increase channel activity. Our results identify two mechanisms leading to regulation of Ca(v)1.2 activity by PKC: pre-association of the channel with PKC isoforms and phosphorylation of specific sites within the alpha(1c) subunit.
Yang
Lin
L
Division of Cardiology, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
Liu
Guoxia
G
Zakharov
Sergey I
SI
Morrow
John P
JP
Rybin
Vitali O
VO
Steinberg
Susan F
SF
Marx
Steven O
SO
D000818:Animals; D001921:Brain / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D015640:Ion Channel Gating; D007527:Isoenzymes / Q000378:metabolism; D046911:Macromolecular Substances / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D009928:Organ Specificity; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism*; D021122:Protein Subunits / Q000378:metabolism; D051381:Rats; D012694:Serine; D015398:Signal Transduction; D013379:Substrate Specificity
D020746:Calcium Channels, L-Type; D007527:Isoenzymes; C419385:L-type calcium channel alpha(1C); D046911:Macromolecular Substances; D021122:Protein Subunits; D012694:Serine; D011493:Protein Kinase C