Regulation of RGS2 and second messenger signaling in vascular smooth muscle cells by cGMP-dependent protein kinase

RGS2, a GTPase-activating protein (GAP) for G(q)alpha, regulates vascular relaxation and blood pressure. RGS2 can be phosphorylated by type I alpha cGMP-dependent protein kinase (cGKI alpha), increasing its GAP activity. To understand how RGS2 and cGKI alpha regulate vascular smooth muscle signaling and function, we identified signaling pathways that are controlled by cGMP in an RGS2-dependent manner and discovered new mechanisms whereby cGK activity regulates RGS2. We show that RGS2 regulates vasoconstrictor-stimulated Ca2+ store release, capacitative Ca2+ entry, and noncapacitative Ca2+ entry and that RGS2 is required for cGMP-mediated inhibition of vasoconstrictor-elicited phospholipase C beta activation, Ca2+ store release, and capacitative Ca2+ entry. RGS2 is degraded in vascular smooth muscle cells via the proteasome. Inhibition of cGK activity blunts RGS2 degradation. However, inactivation of the cGKI alpha phosphorylation sites in RGS2 does not stabilize the protein, suggesting that cGK activity regulates RGS2 degradation by other mechanisms. cGK activation promotes association of RGS2 with the plasma membrane by a mechanism requiring its cGKI alpha phosphorylation sites. By regulating GAP activity, plasma membrane association, and degradation, cGKI alpha therefore may control a cycle of RGS2 activation and inactivation. By diminishing cGK activity, endothelial dysfunction may impair RGS2 activation, thereby blunting vascular relaxation and contributing to hypertension.