Modulation of L-type Ca2+ Channels by Gβγ and Calmodulin via Interactions with N and C Termini of α1C *

By T. Ivanina, Y. Blumenstein, E. Shistik, R. Barzilai, N. Dascal. Journal of Biological Chemistry, 2000

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Neuronal voltage-dependent Ca2+channels of the N (α1B) and P/Q (α1A) type are inhibited by neurotransmitters that activate Gi/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 (α1C) 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 α1C 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 α1C 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 α1C.

Subfields: Cardiology and Cardiovascular Medicine, Cellular and Molecular Neuroscience, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/6ccc910aa7495219acf2b2bbdbe309e87c552be1