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Nat Med. 2003 Dec;9(12):1506-12. Epub 2003 Nov 9.

Regulator of G-protein signaling-2 mediates vascular smooth muscle relaxation and blood pressure.

Author information

  • 1Molecular Cardiology Research Institute, New England Medical Center and Department of Medicine, Tufts University School of Medicine, Boston, Massachusetts 02111, USA.

Erratum in

  • Nat Med. 2004 Jan;10(1):105. Tang, Mary [corrected to Tang, K Mary]; Wang, Guang [corrected to Wang, Guang-rong].


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.

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