Convergent Modulations by Carboxyl-Termini across L-Type Calcium Channel Subtypes

Abstract

L-type calcium channels (LTCCs), also known as CaV1 family, are subject to diverse perturbations while acting as signaling hubs in cells, including autonomous modulations by the distal carboxyl terminus (DCT) of its own. Previous studies show that DCT of CaV1.3 and CaV1.4 (i.e., DCTD and DCTF respectively) competes with calmodulin (CaM) for IQ and IQ vicinity (IQ-IQV) of the channel, which results in attenuation of calcium dependent inactivation (CDI) (Liu et al. 2010). In parallel, DCTC (i.e., DCT of CaV1.2) could autonomously inhibit voltage-gated activation (VGA) of the channel (Hulme et al. 2006). Here, our data demonstrate that distal carboxyl-terminus regulatory domain (DCRD) across CaV1 family could mediate both inhibition of CDI (I-CDI) and inhibition of VGA (I-VGA), suggesting a unified scheme of competitive autoregulation by DCRD across CaV1 family. Thus, the apparent discrepancy in phenotypes of I-CDI and/or I-VGA among CaV1 subtypes can be largely attributed to the different configurations of DCT/IQ-IQV complex. Under such scheme, in addition to well-documented I-VGA, the proteolyzed carboxyl-terminus (CCT) of LTCC in neurons could also induce I-CDI. Both I-VGA and I-CDI play crucial roles in CaV1 signaling in neurons. Our results here provide converged mechanisms across CaV1 channel subtypes in their DCT modulations, highlighting the importance of comparative studies in the context of whole-family of CaV1 channels. Moreover, this study also reveals innovative features from CaV1.1 and CaV1.2, inviting further investigations into mechanism and physiology of DCTs.