AKAP79 modulation of L-type channels involves disruption of intramolecular interactions in the CaV1.2 subunit

L-type voltage gated calcium channels (VGCCs) interact with a variety of proteins that modulate both their function and localization. A-Kinase Anchoring Proteins (AKAPs) facilitate L-type calcium channel phosphorylation through β adrenergic stimulation. Our previous work indicated a role of neuronal AKAP79/150 in the membrane targeting of Ca_V1.2 L-type calcium channels, which involved a proline rich domain (PRD) in the intracellular II-III loop of the channel.¹ Altier C, Dubel SJ, Barrère C, Jarvis SE, Stotz SC, Spaetgens RL, et al. Trafficking of L-type calcium channels mediated by the postsynaptic scaffolding protein AKAP79. J Biol Chem 2002; 277:33598 - 603; http://dx.doi.org/10.1074/jbc.M202476200; PMID: 12114507 Crossref], PubMed], Web of Science ®] , Google Scholar] Here, we show that mutation of proline 857 to alanine (P857A) into the PRD does not disrupt the AKAP79-induced increase in Cav1.2 membrane expression. Furthermore, deletion of two other PRDs into the carboxy terminal domain of Ca_V1.2 did not alter the targeting role of AKAP79. In contrast, the distal carboxy terminus region of the channel directly interacts with AKAP79. This protein-protein interaction competes with a direct association of the channel II-III linker on the carboxy terminal tail and modulates membrane targeting of Ca_V1.2. Thus, our results suggest that the effects of AKAP79 occur through relief of an autoinhibitory mechanism mediated by intramolecular interactions of Cav1.2 intracellular regions.