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

  title={Regulator of G-protein signaling-2 mediates vascular smooth muscle relaxation and blood pressure},
  author={Mary Tang and Guang-rong Wang and Ping Lu and Richard H Karas and Mark J. Aronovitz and Scott P. Heximer and Kevin M Kaltenbronn and Kendall J Blumer and D. Siderovski and Yan Zhu and Michael E. Mendelsohn},
  journal={Nature Medicine},
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… 

cGMP-dependent protein kinase I and smooth muscle relaxation: a tale of two isoforms.

  • H. Surks
  • Biology, Medicine
    Circulation research
  • 2007
After several decades of research, the NO/cGMP/ cGMP-dependent protein kinase (cGK) pathway is now recognized as an important mediator of vasodilation, however, the mechanisms by which cGK causes smooth muscle relaxation continue to be an important question.

Direct Binding and Regulation of RhoA Protein by Cyclic GMP-dependent Protein Kinase Iα*

RhoA is identified as a target of activated PKGIα and shows further that PKGI α binds directly to RhoA, inhibiting its activation and translocation, and that direct binding of activatedPKGIα to RHoA is central to cGMP-mediated inhibition of the VSMC Rho kinase contractile pathway.

RGS2 Is a Mediator of Nitric Oxide Action on Blood Pressure and Vasoconstrictor Signaling

Results indicated that the NO-cGMP pathway uses RGS2 as a novel downstream effector to promote vascular relaxation by attenuating vasoconstrictor-triggered Ca2+ signaling in vascular smooth muscle cells.

Regulation of RGS2 and Second Messenger Signaling in Vascular Smooth Muscle Cells by cGMP-dependent Protein Kinase*

This work has identified signaling pathways that are controlled by cGMP in an RGS2-dependent manner and discovered new mechanisms whereby cGK activity regulates R GS2, and found that RGS 2 is required for cG MP-mediated inhibition of vasoconstrictor-elicited phospholipase Cβ activation, Ca2+ store release, and capacitative Ca2- entry.

Regulator of G-Protein Signaling Subtype 4 Mediates Antihypertrophic Effect of Locally Secreted Natriuretic Peptides in the Heart

Evidence is provided that GC-A activates cardiac RGS4, which attenuates G&agr;q and its downstream hypertrophic signaling, and that R GS4 plays important roles inGC-A-mediated inhibition of cardiac hypertrophy.

cGMP-Dependent Protein Kinases and cGMP Phosphodiesterases in Nitric Oxide and cGMP Action

Current therapies that have successfully targeted the NO-signaling pathway include nitrovasodilators, PDE5 inhibitors, and tadalafil for treatment of a number of vascular diseases including angina pectoris, erectile dysfunction, and pulmonary hypertension, and potential for use of these medications in the treatment of other maladies continues to emerge.

IRAG determines nitric oxide- and atrial natriuretic peptide-mediated smooth muscle relaxation.

Findings indicate that signalling of cGKIbeta via IRAG is an essential functional part for regulation of smooth muscle tone and of intracellular calcium by NO and by ANP.

Fine tuning of blood pressure by the regulator of G protein signaling (RGS) 2.




Role for G(12)/G(13) in agonist-induced vascular smooth muscle cell contraction.

Data indicate that a G(12)/G(13)-mediated Rho/Rho-kinase-dependent pathway operates in smooth muscle cells and that dual regulation of MLC(20) phosphorylation by vasocontractors is initiated by the dual coupling of their receptors to G proteins of the G(q) and G( 12) families.

Phosphorylation and Regulation of G-protein-activated Phospholipase C-β3 by cGMP-dependent Protein Kinases*

The results suggest a molecular mechanism for the regulation of G-protein-mediated intracellular [Ca2+] by the NO-cGMP-dependent signaling pathway.

G-Protein-Coupled Receptors in Vascular Smooth Muscle Cells

The ability of vasoactive peptides to have an impact on signalling cascades mediated by growth factor tyrosine kinase receptors may be important in the pathogenesis of diseases in the vasculature.

Natriuretic Peptides Inhibit G Protein Activation

It is found that atrial natriuretic peptide inhibits the ability of ET-3 to activate Gαq and Gαi in these cells, providing a mechanism by which ANP inhibits downstream signaling to the cell proliferation program.

Mechanism of platelet inhibition by nitric oxide: in vivo phosphorylation of thromboxane receptor by cyclic GMP-dependent protein kinase.

TXA2 receptors are identified as cGMP-dependent protein kinase substrates and support a novel mechanism for the inhibition of cell function by NO in which activation of G kinase inhibits signaling by G protein-coupled receptors by catalyzing their phosphorylation.

Defective smooth muscle regulation in cGMP kinase I‐deficient mice

It is shown that cAMP and cGMP signal via independent pathways, with cGKI being the specific mediator of the NO/cGMP effects in murine smooth muscle.

Hypertension and prolonged vasoconstrictor signaling in RGS2-deficient mice.

It is established that abnormally prolonged signaling by G protein-coupled vasoconstrictor receptors can contribute to the onset of hypertension, and it is suggested that genetic defects affecting the function or expression of RGS2 may be novel risk factors for development of hypertension in humans.

Regulation of intracellular calcium by a signalling complex of IRAG, IP3 receptor and cGMP kinase Iβ

IRAG is identified as an essential NO/ cGKI-dependent regulator of IP3-induced calcium release and contributes to the antiproliferative and pro-apoptotic effects of NO/cGMP.

Hypertension in mice lacking the gene for endothelial nitric oxide synthase

Responses to NOS blockade in the mutant mice suggest that non-endothelial isoforms of NOS may be involved in maintaining blood pressure, and eNOS mediates basal vasodilation.

Functional Reconstitution of Vascular Smooth Muscle Cells With cGMP-Dependent Protein Kinase I Isoforms

Results suggest that one component of NO/cGMP-induced smooth muscle relaxation is the activation of the cGKI&agr; isoform, which decreases the noradrenaline-stimulated cytosolic Ca2+ level.