Ser1928 is a common site for Cav1.2 phosphorylation by protein kinase C isoforms

Abstract

Voltage-dependent Ca2+ channel (Cav1.2, L-type Ca2+ channel) function is highly regulated by hormones and neurotransmitters in large part through the activation of kinases and phosphatases. Regulation of Cav1.2 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 Cav1.2 function, the molecular mechanisms mediating the response have not been definitively elucidated. We show that PKC forms a macromolecular complex with the α1c subunit of Ca v1.2 through direct interaction with the C terminus. This interaction leads to phosphorylation of the channel in response to activators of PKC. We identify Ser1928 as the residue that is phosphorylated by PKC in vitro and in vivo. Ser1928 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 v1.2 complex at Ser1928 to increase channel activity. Our results identify two mechanisms leading to regulation of Cav1.2 activity by PKC: pre-association of the channel with PKC isoforms and phosphorylation of specific sites within the α1c subunit.