Regulator of G-protein signaling-2 mediates vascular smooth muscle relaxation and blood pressure.
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.
Tang
K Mary
KM
Molecular Cardiology Research Institute, New England Medical Center and Department of Medicine, Tufts University School of Medicine, Boston, Massachusetts 02111, USA.
Wang
Guang-rong
GR
Lu
Ping
P
Karas
Richard H
RH
Aronovitz
Mark
M
Heximer
Scott P
SP
Kaltenbronn
Kevin M
KM
Blumer
Kendall J
KJ
Siderovski
David P
DP
Zhu
Yan
Y
Mendelsohn
Michael E
ME
Tang
Mary
M
Wang
Guang
G
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
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