Endotoxin induces desensitization of cardiac endothelin-1 receptor signaling by increased expression of RGS4 and RGS16

Patten, Monica; Bünemann, J.; Thoma, Bryan; Krämer, Elisabeth; Thoenes, Martin; Stübe, Sabine; Mittmann, Clemens; Wieland, Thomas

doi:10.1016/s0008-6363(01)00443-6

Cited by 29 publications

(26 citation statements)

References 32 publications

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“…Again, mRNA expression of RGS16 was up-regulated by LPS exposure whereas RGS2, RGS3, RGS4 and RGS5 expression levels were also unaffected. These data are in line with the reported transient increase in RGS16 mRNA and protein expression in rat hearts and cultured neonatal cardiomyocytes after LPS treatment (21). Also in pig heart and aorta an up-regulation of RGS16 mRNA expression upon LPS exposure has been described (19).…”

Section: Discussionsupporting

confidence: 87%

“…Previous studies have suggested a role for RGS4 and RGS16 in the early onset of cardiac failure during septic shock (21). Probably, alterations in RGS protein expression also play a role in the hypotension associated with LPS treatment and the hypo-responsiveness of several vasoconstrictors.…”

Section: Discussionmentioning

confidence: 97%

“…PATTEN et al (21) showed that LPSinduced cardiac failure is associated with alterations in regulator of G protein signalling (RGS) proteins, especially in RGS4 and RGS16 expression. RGS proteins are a family of intracellular proteins that are able to fine-tune G protein-coupled receptor (GPCR) signalling either by acting as GTPase activating proteins for the Gα subunits or by providing a signalling network through protein-protein interactions with various signalling proteins (for review see (11,14,22,26)).…”

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confidence: 99%

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Diversos efectos vasoconstrictores del LPS: un posible papel para RGS16?

Hendriks-Balk

Tjon-Atsoi

Hajji

et al. 2009

J. Physiol. Biochem.

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The profound hypotension in septic shock patients is difficult to treat as it is accompanied by depressed constrictor responses to alpha1-adrenoceptor agonists. Bacterial lipopolysaccharide (LPS) is the main trigger for most of the cardiovascular alterations occurring in septic shock. In this study we investigated the effects of LPS exposure on vascular contractility in general and the role of Regulator of G protein Signalling (RGS) proteins in the LPS-induced vascular alterations. Exposure of rat aortic rings to various LPS concentrations (3, 10, 30 microg/ml) for 22 hours differentially affected agonist-induced contractile responses at four distinct G-protein coupled receptors (alpha1-adrenoceptors, angiotensin II, serotonin and endothelin-1 receptors). While the endothelin-1-induced contraction was unaffected by LPS pre-treatment, phenylephrine- and angiotensin II-induced contraction were significantly reduced whereas serotonin-induced contraction was significantly enhanced. Concomitantly, LPS treatment increased the RGS16 mRNA expression both in aortic rings and cultured vascular smooth muscle cells (VSMCs) but not that of RGS2, RGS3, RGS4 or RGS5. The significant increase in RGS16 mRNA expression in VSMCs by LPS was time- and concentration-dependent but independent of increased inducible NO synthase (iNOS) activity. The changes in RGS16 mRNA might contribute to the differential regulation of the contractile responses to vasoconstrictors upon LPS exposure.

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Section: Discussionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 97%

mentioning

confidence: 99%

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Diversos efectos vasoconstrictores del LPS: un posible papel para RGS16?

Hendriks-Balk

Tjon-Atsoi

Hajji

et al. 2009

J. Physiol. Biochem.

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“…We have previously carried out a degenerate RT-PCR screen in the hearts of a porcine model of sepsis and have thus identified both RGS1 and RGS16 as being upregulated [168]. Similarly, Wieland's group found that R4 RGSs, including RGS16 and RGS4 were upregulated in the septic heart [70,169]. They further demonstrated that overexpression of RGS16 was sufficient to attenuate endothelin-1 signalling in the heart.…”

Section: Altered Rgs Expression Is Associated With Pathophysiologicalmentioning

confidence: 95%

Regulatory mechanisms involved in modulating RGS function

Jean-Baptiste

Yang

Greenwood

2006

Cell. Mol. Life Sci.

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Regulator of G-Protein Signaling (RGS) refers to a conserved 120-125 amino acid motif that was first identified by its ability to negatively regulate G-Protein-Coupled Receptor (GPCR) signalling. Mechanistically, RGSs were found to regulate GPCR responses by binding to and stimulating the GTPase activity of the receptor-activated GTP-bound G alpha subunits. There are now over 25 mammalian RGSs containing proteins that are reported to carry out a variety of functions, many of which are unrelated to GPCR signalling. RGS proteins range in size from small proteins that contain little more than an RGS box to very large proteins that contain a variety of domains. The selectivity of function of the RGS proteins is attributable to the divergence of the RGS sequences as well as the presence of a variety of functional motifs, which allow them to interact with other proteins. Here we focus on the RGSs that are involved in modulating GPCR signalling by reviewing the diversity of the mechanisms involved in regulating these RGSs.

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“…RGS4 plays an important role in promoting cardiac development, regulating neuronal plasticity, and modulating smooth muscle contraction (2). In cardiomyocytes, RGS4 expression is induced by endotoxin and interleukin (IL)-1␤ (57,58) and contributes to the loss of G␣ q -mediated activation of phospholipase C (PLC) by endothelin-1 (51). In the central nervous system, RGS4 is linked to schizophrenia (6,14,27,44,46), Alzheimer disease (13), and Huntington disease (63).…”

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confidence: 99%

RNA-binding protein HuR regulates RGS4 mRNA stability in rabbit colonic smooth muscle cells

Liu

et al. 2010

American Journal of Physiology-Cell Physiology

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September 29, 2010; doi:10.1152/ajpcell.00093.2010.-Regulator of G protein signaling 4 (RGS4) regulates the strength and duration of G protein signaling and plays an important role in smooth muscle contraction, cardiac development, and psychiatric disorders. Little is known about the posttranscriptional regulation of RGS4 expression. We cloned the full-length cDNA of rabbit RGS4, which contains a long 3=-untranslated region (UTR) with several AU-rich elements (AREs). We determined whether RGS4 mRNA stability is mediated by the RNA-binding protein human antigen R (HuR) and contributes to IL-1␤-induced upregulation of RGS4 expression. We show that IL-1␤ treatment in colonic smooth muscle cells doubled the half-life of RGS4 mRNA. Addition of RGS4 3=-UTR to the downstream of Renilla luciferase reporter induced dramatic reduction in the enzyme activity and mRNA expression of luciferase, which was attenuated by the site-directed mutation of the two 3=-most ARE sites. IL-1␤ increased luciferase mRNA stability in a UTR-dependent manner. Knockdown of HuR significantly aggravated UTR-mediated instability of luciferase and inhibited IL-1␤-induced upregulation of RGS4 mRNA. In addition, IL-1␤ increased cytosolic translocation and RGS4 mRNA binding of HuR. These findings suggest that 3=-most ARE sites within RGS4 3=-UTR are essential for the instability of RGS4 mRNA and IL-1␤ promotes the stability of RGS4 mRNA through HuR.regulators of G protein signaling; Interleukin; AU-rich element REGULATOR OF G PROTEIN SIGNALING (RGS) proteins belong to a large family of highly diverse, multifunctional signaling proteins, which share a conserved signature domain (RGS domain) that binds directly to the activated G␣ subunits. RGS terminates G protein signaling by accelerating intrinsic GTPase activity of G␣ and thereby fostering reassociation of the G␣␤␥ trimer (61). Over 30 mammalian family members have been described so far and classified into seven subfamilies based on sequence identity and functional similarities (70,72). RGS4 is one of the most extensively studied RGS proteins (44,61,62,70,72) and regulates the strength and duration of the G␣ i/o and G␣ q/11 family members (26, 36). RGS4 plays an important role in promoting cardiac development, regulating neuronal plasticity, and modulating smooth muscle contraction (2). In cardiomyocytes, RGS4 expression is induced by endotoxin and interleukin (IL)-1␤ (57, 58) and contributes to the loss of G␣ q -mediated activation of phospholipase C (PLC) by endothelin-1 (51). In the central nervous system, RGS4 is linked to schizophrenia (6,14,27,44,46), Alzheimer disease (13), and Huntington disease (63). RGS4 regulates the pain process (17, 25) and morphine tolerance (25, 31) through modulation of opioid receptor signaling (43,69). In gastrointestinal smooth muscle, RGS4 negatively regulates G␣ q signaling activated by M3 or motilin receptors (37, 38) and thus inhibits agonistinduced initial contraction (33,35,36). Recently, we demonstrated (35) that treatment of colonic smooth muscle cells ...

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Endotoxin induces desensitization of cardiac endothelin-1 receptor signaling by increased expression of RGS4 and RGS16

Abstract: These data suggest that the rapid up-regulation of cardiac RGS4 and RGS16 is associated with a desensitization of endothelin-1 receptor signaling. Up-regulation of these RGS proteins may thus be involved in the early onset of cardiac failure during sepsis.

Cited by 29 publications

References 32 publications

Diversos efectos vasoconstrictores del LPS: un posible papel para RGS16?

Diversos efectos vasoconstrictores del LPS: un posible papel para RGS16?

Regulatory mechanisms involved in modulating RGS function

RNA-binding protein HuR regulates RGS4 mRNA stability in rabbit colonic smooth muscle cells

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