Unified mechanisms of Ca2+ regulation across the Ca2+ channel family

L-type (Ca(V)1.2) and P/Q-type (Ca(V)2.1) calcium channels possess lobe-specific CaM regulation, where Call binding to one or the other lobe of CaM triggers regulation, even with inverted polarity of modulation between channels. Other major members of the Ca(V)1-2 channel family, R-type (Ca(V)2.3) and N-type (Ca(V)2.2), have appeared to lack such CaM regulation. We report here that R- and N-type channels undergo Ca2+-dependent inactivation, which is mediated by the CaM N-terminal lobe and present only with mild Ca2+ buffering (0.5 mM EGTA) characteristic of many neurons. These features, together with the CaM regulatory profiles of L- and P/Q-type channels, are consistent with a simplifying principle for CaM signal detection in Ca(V)1-2 channels-independent of channel context, the N- and C-terminal lobes of CaM appear invariably specialized for decoding local versus global Ca2+ activity, respectively.