CaBP1 Regulates Voltage-dependent Inactivation and Activation of CaV1.2 (L-type) Calcium Channels

CaBP1 is a Ca2+-binding protein that regulates the gating of voltage-gated (Ca-V) Ca2+ channels. In the Ca(V)1.2 channel alpha(1)-subunit (alpha(1C)), CaBP1 interacts with cytosolic N- and C-terminal domains and blunts Ca2+-dependent inactivation. To clarify the role of the alpha(1C) N-terminal domain in CaBP1 regulation, we compared the effects of CaBP1 on two alternatively spliced variants of alpha(1C) containing a long or short N-terminal domain. In both isoforms, CaBP1 inhibited Ca2+-dependent inactivation but also caused a depolarizing shift in voltage-dependent activation and enhanced voltage-dependent inactivation (VDI). In binding assays, CaBP1 interacted with the distal third of the N-terminal domain in a Ca2+-independent manner. This segment is distinct from the previously identified calmodulin-binding site in the N terminus. However, deletion of a segment in the proximal N-terminal domain of both alpha(1C) isoforms, which spared the CaBP1-binding site, inhibited the effect of CaBP1 on VDI. This result suggests a modular organization of the alpha(1C) N-terminal domain, with separate determinants for CaBP1 binding and transduction of the effect on VDI. Our findings expand the diversity and mechanisms of Ca-V channel regulation by CaBP1 and define a novel modulatory function for the initial segment of the N terminus of alpha(1C).