Modulation of L-type Ca²⁺ channels by Gβγ and calmodulin via interactions with N and C termini of α_1c

Neuronal voltage-dependent Ca²⁺ channels of the N (α_1B) and P/Q (α_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 Gβγ subunit of G proteins to the channel. Since cardiac and neuronal L-type (α_1C) voltage-dependent Ca²⁺ channels are not modulated in this way, they are presumed to lack interaction with Gβγ. However, here we demonstrate that both Gβγ and calmodulin directly bind to cytosolic N and C termini of the α_1C subunit. Coexpression of Gβγ 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 α_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 Gβγ. Deletion of the N terminus profoundly impairs the Ca²⁺/calmodulin-dependent inactivation. We propose that Gβγ and calmodulin regulate the L-type Ca²⁺ channel in a concerted manner via a molecular inhibitory scaffold formed by N and C termini of α_1C.