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-α (PKGI-α), which causes dephosphorylation of myosin light chain (MLC) and vascular smooth muscle relaxation. Here we show that PKGI-α attenuates signaling by the thrombin receptor protease-activated recept...
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Veröffentlicht in: | Nature medicine 2003-12, Vol.9 (12), p.1506-1512 |
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Sprache: | eng |
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Zusammenfassung: | Nitric oxide (NO) inhibits vascular contraction by activating cGMP-dependent protein kinase I-α (PKGI-α), which causes dephosphorylation of myosin light chain (MLC) and vascular smooth muscle relaxation. Here we show that PKGI-α 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-α 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-α 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-α 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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ISSN: | 1078-8956 1546-170X |
DOI: | 10.1038/nm958 |