Hypertension and prolonged vasoconstrictor signaling in RGS2-deficient mice

Heximer, Scott P.; Knutsen, Russell H.; Sun, Xiaoguang; Kaltenbronn, Kevin M.; Rhee, Man Hee; Ning, Peng; Oliveira-dos-Santos, Antonio J.; Penninger, Josef; Muslin, Anthony J.; Steinberg, Thomas H.; Wyss, J. Michael; Mecham, Robert P.; Blumer, Kendall J.

doi:10.1172/jci15598

Cited by 244 publications

(80 citation statements)

References 41 publications

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“…Our findings stand in contrast to those of Heximer et al (39), who studied calcium responses in aortic smooth muscle cells isolated from wild type and rgs2 Ϫ/Ϫ mice. Under basal conditions, peak calcium responses were greater in cells derived from rgs2 Ϫ/Ϫ as compared with wild type animals (39).…”

Section: Discussioncontrasting

confidence: 99%

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Up-regulation of Endogenous RGS2 Mediates Cross-desensitization between Gs and Gq Signaling in Osteoblasts

Roy

Nunn

Hong

et al. 2006

Journal of Biological Chemistry

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Regulator of G protein signaling (RGS) proteins limitG protein-coupled receptors (GPCRs) 6 respond to a variety of hormones, paracrine factors, and neurotransmitters by activating heterotrimeric G proteins. Upon activation of the G protein, G␣ is stimulated to exchange bound GDP for cytosolic GTP and is thought to subsequently dissociate from the ␤␥ dimer. Both G␣ and the ␤␥ dimer are then capable of interacting with cellular effectors for a period of time that is limited by the intrinsic GTPase activity of the G␣ subunit. Regulator of G protein signaling (RGS) proteins can reduce the duration of these interactions by increasing the rate of GTP hydrolysis by the G␣ subunits, or by otherwise blocking interactions between G␣ and its target enzymes through a poorly understood process sometimes referred to as "effector antagonism" (1, 2).G protein signaling in osteoblasts is a critical regulator of bone formation. The predominant GPCRs expressed by osteoblasts include the parathyroid hormone (PTH)/parathyroid hormone-related peptide (PTHrP) receptor type 1 (PTH1R), P2Y nucleotide receptors, and prostaglandin receptors (3). Other GPCRs found in osteoblasts include endothelin, adenosine, ␤-adrenergic, angiotensin II, and calcium-sensing receptors (3, 4). Binding of PTH to its specific receptor, PTH1R, predominantly leads to the activation of G s (although under certain conditions the receptor can also couple to G q and G i ) (5, 6). Activated G s stimulates adenylyl cyclase to generate intracellular cAMP, which results in the activation of protein kinase A. Stimulation of G q promotes the activity of phospholipase C-␤ (PLC-␤), resulting in the accumulation of inositol 1,4,5-trisphosphate and diacylglycerol, which lead, respectively, to release of calcium from intracellular stores and activation of protein kinase C. Nucleotide stimulation of P2Y receptors in osteoblasts results in PLC-␤ activation and calcium mobilization, with no effect on adenylyl cyclase (3, 7).

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Section: Discussioncontrasting

confidence: 99%

“…Under basal conditions, peak calcium responses were greater in cells derived from rgs2 Ϫ/Ϫ as compared with wild type animals (39). It follows that the role of RGS2 in regulating G q signals varies from one cell type to another.…”

Section: Discussionmentioning

confidence: 85%

Up-regulation of Endogenous RGS2 Mediates Cross-desensitization between Gs and Gq Signaling in Osteoblasts

Roy

Nunn

Hong

et al. 2006

Journal of Biological Chemistry

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“…8A). These observations raise the possibility that the three human RGS2 SNPs might negatively affect RGS2 mRNA expression, which might be expected to predispose to hypertension by analogy with effects of reduced RGS2 expression on blood pressure in genetically modified mice (3)(4)(5)(6)(7).…”

Section: Snps Identified In Human Hypertensive Patients Are Located Imentioning

confidence: 99%

“…RGS2 is expressed ubiquitously, and its major biological function is to serve as a GTPase-activating protein that preferentially attenuates heterotrimeric G protein G␣ q/11 GTPase activity (2). Several independent studies have demonstrated that Rgs2 knock-out mice have severe hypertension (3)(4)(5)(6)(7), suggesting that RGS2 plays a critical role in blood pressure homeostasis. Interestingly, heterozygous Rgs2 knockout mice are also hypertensive, and their blood pressures are virtually identical to homozygous Rgs2 knock-out mice (3), indicating that two functional Rgs2 alleles are required for normal blood pressure homeostasis.…”

mentioning

confidence: 99%

Identification of a cAMP-response Element in the Regulator of G-protein Signaling-2 (RGS2) Promoter as a Key Cis-regulatory Element for RGS2 Transcriptional Regulation by Angiotensin II in Cultured Vascular Smooth Muscles

Xie

Liu

et al. 2011

Journal of Biological Chemistry

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Background: Angiotensin II-induced regulator of G-protein signaling-2 (RGS2) expression is an important negative feedback loop in blood pressure homeostasis. Results: A conserved cAMP-response element-binding protein (CREB) binding site is found in the RGS2 promoter and is associated with three SNPs identified in hypertensive patients. Conclusion: CREB links the angiotensin II/PKC/iPLA 2 ␤/PKA signaling and RGS2 transcription. Significance: This study delineates a negative feedback loop with potential importance in the pathogenesis of human hypertension.

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“…RGS2 also functions as a GAP for G i (Ingi et al, 1998;Hains et al, 2004) and may produce inhibitory effects on G s -mediated adenylate cyclase activity via binding to adenylate cyclase (Sinnarajah et al, 2001;Salim et al, 2003). Functions of RGS2 in the immune, neurological and cardiovascular systems are well established utilizing RGS2-deficient mice (Oliveira-Dos- Santos et al, 2000;Heximer et al, 2003;Tang et al, 2003). A recent study suggests that RGS2 appears to be a locus implicated in solid tumor development (Collier et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Regulator of G-protein signaling 2 (RGS2) inhibits androgen-independent activation of androgen receptor in prostate cancer cells

et al. 2006

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Expression of RGS2, but not other RGS proteins, abolished androgen-independent AR activity in androgenindependent LNCaP cells and CWR22Rv1 cells. In LNCaP cells, RGS2 inhibited G q -coupled GPCR signaling. Expression of exogenous wild-type RGS2, but not its GAP-deficient mutant, significantly reduced AR activation by constitutively activated G q Q209L mutant whereas silencing endogenous RGS2 by siRNA enhanced G q Q209L-stimulated AR activity. RGS2 had no effect on RGS-insensitive G q Q209L/G188S-induced AR activation. Furthermore, extracellular signal-regulated kinase 1/2 (ERK1/2) was found to be involved in RGS2-mediated regulation of androgen-independent AR activity. In addition, RGS2 functioned as a growth suppressor for androgen-independent LNCaP cells whereas androgensensitive LNCaP cells with RGS2 silencing had a growth advantage under steroid-reduced conditions. Finally, RGS2 expression level was significantly decreased in human prostate tumor specimens. Taken together, our results suggest RGS2 as a novel regulator of AR signaling and its repression may be an important step during prostate tumorigenesis and progression.

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Hypertension and prolonged vasoconstrictor signaling in RGS2-deficient mice

Cited by 244 publications

References 41 publications

Up-regulation of Endogenous RGS2 Mediates Cross-desensitization between Gs and Gq Signaling in Osteoblasts

Up-regulation of Endogenous RGS2 Mediates Cross-desensitization between Gs and Gq Signaling in Osteoblasts

Identification of a cAMP-response Element in the Regulator of G-protein Signaling-2 (RGS2) Promoter as a Key Cis-regulatory Element for RGS2 Transcriptional Regulation by Angiotensin II in Cultured Vascular Smooth Muscles

Regulator of G-protein signaling 2 (RGS2) inhibits androgen-independent activation of androgen receptor in prostate cancer cells

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