A new interaction between proximal and distal C-terminus of Cav1.2 channels

Cardiac Cav1.2 channels, coupling membrane stimulation to intracellular Ca²⁺ signaling, are regulated by multiple cytoplasmic factors, such as calmodulin (CaM), phosphorylation, Ca²⁺, ATP and intramolecular fragments of the channel. The interaction between distal and proximal C-terminal regulatory domains (DCRD and PCRD) of Cav1.2 channel is suggested to inhibit the channel activity, while PKA-mediated phosphorylation facilitates Cav1.2 channel by releasing such an interaction. Here, we report that the interaction between the distal C-terminus (CT3) and the proximal C-terminus (CT1) are inhibited by CaM in a Ca²⁺-dependent manner. Furthermore, CT3D (a short CT3 with DCRD truncated) interacts with CT1B (a short CT1 with EF-hand and PCRD truncated), revealing a new interaction between distal and proximal C-terminus. Ca²⁺/CaM inhibited the binding of CT3D to CT1B more strongly than the binding between CT3 and CT1, implying that the interaction of DCRD/PCRD (in CT3/CT1) might cooperate with the binding of CT3D to CT1B. We name the new CT1B-binding region of CT3D as CaM-competitive domain (CCD). The electrophysiological experiments show that CT3D inhibits while CT1B facilitates Cav1.2 channel activity in inside-out patches in guinea-pig ventricular myocytes. These results suggest that distal C-terminus inhibits Cav1.2 channel through modulation of the CaM-binding property of the channels.