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. © 2017 the authors