title: Regulator of G-protein signaling-2 mediates vascular smooth muscle relaxation and blood pressure.
abstract: Nitric oxide (NO) inhibits vascular contraction by activating cGMP-dependent protein kinase I-alpha (PKGI-alpha), which causes dephosphorylation of myosin light chain (MLC) and vascular smooth muscle relaxation. Here we show that PKGI-alpha attenuates signaling by the thrombin receptor protease-activated receptor-1 (PAR-1) through direct activation of regulator of G-protein signaling-2 (RGS-2). NO donors and cGMP cause cGMP-mediated inhibition of PAR-1 and membrane localization of RGS-2. PKGI-alpha binds directly to and phosphorylates RGS-2, which significantly increases GTPase activity of G(q), terminating PAR-1 signaling. Disruption of the RGS-2-PKGI-alpha interaction reverses inhibition of PAR-1 signaling by nitrovasodilators and cGMP. Rgs2-/- mice develop marked hypertension, and their blood vessels show enhanced contraction and decreased cGMP-mediated relaxation. Thus, PKGI-alpha binds to, phosphorylates and activates RGS-2, attenuating receptor-mediated vascular contraction. Our study shows that RGS-2 is required for normal vascular function and blood pressure and is a new drug development target for hypertension.
authors: Molecular Cardiology Research Institute, New England Medical Center and Department of Medicine, Tufts University School of Medicine, Boston, Massachusetts 02111, USA.
authors: K Mary
authors: KM
authors: Tang
authors: Guang-rong
authors: GR
authors: Wang
authors: Ping
authors: P
authors: Lu
authors: Richard H
authors: RH
authors: Karas
authors: Mark
authors: M
authors: Aronovitz
authors: Scott P
authors: SP
authors: Heximer
authors: Kevin M
authors: KM
authors: Kaltenbronn
authors: Kendall J
authors: KJ
authors: Blumer
authors: David P
authors: DP
authors: Siderovski
authors: Yan
authors: Y
authors: Zhu
authors: Michael E
authors: ME
authors: Mendelsohn
authors: Mary
authors: M
authors: Tang
authors: Guang
authors: G
authors: Wang
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000502:physiology*; D002460:Cell Line; D062965:Cyclic GMP-Dependent Protein Kinase Type I; D017869:Cyclic GMP-Dependent Protein Kinases / Q000502:physiology; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009126:Muscle Relaxation / Q000502:physiology*; D009131:Muscle, Smooth, Vascular / Q000502:physiology*; D020710:RGS Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051381:Rats; D044463:Receptor, PAR-1 / Q000502:physiology; D015398:Signal Transduction
chemical_list: D020710:RGS Proteins; D044463:Receptor, PAR-1; C105345:Rgs2 protein, mouse; D062965:Cyclic GMP-Dependent Protein Kinase Type I; D017869:Cyclic GMP-Dependent Protein Kinases; C569718:PRKG1 protein, human; C569720:Prkg1 protein, mouse