TY - JOUR
T1 - Regulation of RGS2 and second messenger signaling in vascular smooth muscle cells by cGMP-dependent protein kinase
AU - Osei-Owusu, Patrick
AU - Sun, Xiaoguang
AU - Drenan, Ryan M.
AU - Steinberg, Thomas H.
AU - Blumer, Kendall J.
PY - 2007/10/26
Y1 - 2007/10/26
N2 - RGS2, a GTPase-activating protein (GAP) for Gqα, regulates vascular relaxation and blood pressure. RGS2 can be phosphorylated by type Iα cGMP-dependent protein kinase (cGKIα), increasing its GAP activity. To understand how RGS2 and cGKIα 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 Cβ 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 cGKIα 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 cGKIα phosphorylation sites. By regulating GAP activity, plasma membrane association, and degradation, cGKIα 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.
AB - RGS2, a GTPase-activating protein (GAP) for Gqα, regulates vascular relaxation and blood pressure. RGS2 can be phosphorylated by type Iα cGMP-dependent protein kinase (cGKIα), increasing its GAP activity. To understand how RGS2 and cGKIα 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 Cβ 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 cGKIα 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 cGKIα phosphorylation sites. By regulating GAP activity, plasma membrane association, and degradation, cGKIα 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.
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U2 - 10.1074/jbc.M706360200
DO - 10.1074/jbc.M706360200
M3 - Article
C2 - 17681944
AN - SCOPUS:35748984127
SN - 0021-9258
VL - 282
SP - 31656
EP - 31665
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 43
ER -