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Modulation of distinct isoforms of L-type calcium channels by Gq-coupled receptors in Xenopus oocytes: Antagonistic effects of Gβγ and protein kinase C.
Weiss S, Keren-Raifman T, Oz S, Ben Mocha A, Haase H, Dascal N.
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L-type voltage dependent Ca ( 2+) channels (L-VDCCs; Cav 1.2) are crucial in cardiovascular physiology. In heart and smooth muscle, hormones and transmitters operating via Gq enhance L-VDCC currents via essential protein kinase C (PKC) involvement. Heterologous reconstitution studies in Xenopus oocytes suggested that PKC and Gq-coupled receptors increased L-VDCC currents only in cardiac long N-terminus (NT) isoforms of α 1C, whereas known smooth muscle short-NT isoforms were inhibited by PKC and Gq activators. We report a novel regulation of the long-NT α 1C isoform by Gβγ. Gβγ inhibited whereas a Gβγ scavenger protein augmented the Gq- but not phorbol ester-mediated enhancement of channel activity, suggesting that Gβγ acts upstream from PKC. In vitro binding experiments reveal binding of both Gβγ and PKC to α 1C-NT. However, PKC modulation was not altered by mutations of multiple potential phosphorylation sites in the NT, and was attenuated by a mutation of C-terminally located serine S1928. The insertion of exon 9a in intracellular loop 1 rendered the short-NT α 1C sensitive to PKC stimulation and to Gβγ scavenging. Our results suggest a complex antagonistic interplay between Gq-activated PKC and Gβγ in regulation of L-VDCC, in which multiple cytosolic segments of α 1C are involved.
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