Functional Roles of a C-terminal Signaling Complex of Cav1 Channels and A-kinase Anchoring Protein 15 in Brain Neurons

Regulation of Ca(V)1.2 channels in cardiac myocytes by the beta-adrenergic pathway requires a signaling complex in which the proteolytically processed distal C-terminal domain acts as an autoinhibitor of channel activity and mediates up-regulation by the beta-adrenergic receptor and PKA bound to A-kinase anchoring protein 15 (AKAP15). We examined the significance of this distal C-terminal signaling complex for Ca(V)1.2 and Ca(V)1.3 channels in neurons. AKAP15 co-immunoprecipitates with Ca(V)1.2 and Ca(V)1.3 channels. AKAP15 has overlapping localization with Ca(V)1.2 and Ca(V)1.3 channels in cell bodies and proximal dendrites and is closely co-localized with Ca(V)1.2 channels in punctate clusters. The neuronal AKAP MAP2B, which also interacts with Ca(V)1.2 and Ca(V)1.3 channels, has complementary localization to AKAP15, suggesting different functional roles in calcium channel regulation. Studies with mice that lack the distal C-terminal domain of Ca(V)1.2 channels (Ca(V)1.2 Delta DCT) reveal that AKAP15 interacts with neuronal Ca(V)1.2 channels via their C terminus in vivo and is co-localized in punctate clusters of Ca(V)1.2 channels via that interaction. Ca(V)1.2 Delta DCT neurons have reduced L-type calcium current, indicating that the distal C-terminal domain is required for normal functional expression in vivo. Deletion of the distal C-terminal domain impairs calcium- dependent signaling from Ca(V)1.2 channels to the nucleus, as shown by reduction in phosphorylation of the cAMP response element-binding protein. Our results define AKAP signaling complexes of Ca(V)1.2 and Ca(V)1.3 channels in brain and reveal three previously unrecognized functional roles for the distal C terminus of neuronal Ca(V)1.2 channels in vivo: increased functional expression, anchoring of AKAP15 and PKA, and initiation of excitation-transcription coupling.