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 Ialpha cGMP-dependent protein kinase (cGKIalpha), increasing its GAP activity. To understand how RGS2 and cGKIalpha 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 Ca(2+) store release, capacitative Ca(2+) entry, and noncapacitative Ca(2+) entry and that RGS2 is required for cGMP-mediated inhibition of vasoconstrictor-elicited phospholipase Cbeta activation, Ca(2+) store release, and capacitative Ca(2+) entry. RGS2 is degraded in vascular smooth muscle cells via the proteasome. Inhibition of cGK activity blunts RGS2 degradation. However, inactivation of the cGKIalpha 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 cGKIalpha phosphorylation sites. By regulating GAP activity, plasma membrane association, and degradation, cGKIalpha 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.
Cell Biology and Physiology and Internal Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Patrick
P
Osei-Owusu
Xiaoguang
X
Sun
Ryan M
RM
Drenan
Thomas H
TH
Steinberg
Kendall J
KJ
Blumer
D000818:Animals; D001013:Aorta, Thoracic / Q000166:cytology; D002478:Cells, Cultured; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism*; D019084:Fluorescent Antibody Technique, Indirect; D015971:Gene Expression Regulation, Enzymologic; D005822:Genetic Vectors; D016086:Lentivirus / Q000235:genetics; D051379:Mice; D008856:Microscopy, Fluorescence; D008958:Models, Molecular; D009131:Muscle, Smooth, Vascular / Q000502:physiology*; D020710:RGS Proteins / Q000502:physiology*; D015290:Second Messenger Systems / Q000502:physiology*
D020710:RGS Proteins; C105345:Rgs2 protein, mouse; D017869:Cyclic GMP-Dependent Protein Kinases