Modulation of L-type Ca2+ channels by Gβγ and calmodulin via interactions with N and C termini of α1C

Neuronal voltage-dependent Ca2+ channels of the N (alpha (1B)) and P/Q (alpha (1A)) type are inhibited by neurotransmitters that activate G(i/o) G proteins; a major part of the inhibition is voltage-dependent, relieved by depolarization, and results from a direct binding of G beta gamma subunit of G proteins to the channel. Since cardiac and neuronal L-type (alpha (1C)) voltage-dependent Ca2+ channels are not modulated in this way, they are presumed to lack interaction with G beta gamma. However, here we demonstrate that both G beta gamma and cahmodulin directly bind to cytosolic N and C termini of the alpha (1C) subunit. Coexpression of G beta gamma reduces the current via the L-type channels. The inhibition depends on the presence of calmodulin, occurs at basal cellular levels of Ca2+, and is eliminated by EGTA. The N and C termini of alpha (1C) appear to serve as partially independent but interacting inhibitory gates. Deletion of the N terminus or of the distal half of the C terminus eliminates the inhibitory effect of G beta gamma. Deletion of the N terminus profoundly impairs the Ca2+/calmodulin-dependent inactivation. We propose that G beta gamma and calmodulin regulate the L-type Ca2+ channel in a concerted manner via a molecular inhibitory scaffold formed by N and C termini of alpha (1C).