Protein kinase C forms a macromolecular complex with the alpha1c subunit of Cav1.2 and phosphorylates it at Ser1928, converging with protein kinase A signaling to increase channel activity.
Identifies Ser1928 as a critical convergence point for PKA and PKC phosphorylation on the Cav1.2 channel, explaining a key mechanism of cardiac hormonal regulation.
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 et al. (Thu,) reported a other. Protein kinase C forms a macromolecular complex with the alpha1c subunit of Cav1.2 and phosphorylates it at Ser1928, converging with protein kinase A signaling to increase channel activity.