• The Korean Journal of Pain
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• v.19 no.1
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• pp.8-16
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• 2006

The regulators of the G protein signaling (RGS) proteins are responsible for the rapid acceleration of the GTPase-activity intrinsic to the heterotrimeric G protein alpha subunits. As GTPase-activating proteins (GAP), the RGS proteins negatively regulate the G-protein signals. Recently, the RGS proteins are known to be one of the important regulators of opioid signal transduction and the development of tolerance. The aim of this study was to review the recent discovery and understanding of the role of RGS proteins in opioid signaling and the development of tolerance. This information will be useful for medical personnel, particularly those involved in anesthesia and pain medicine, by helping them improve the effective use of opioids and develop new drugs that can prevent opioid tolerance.

• The Korean Journal of Physiology and Pharmacology
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• v.15 no.6
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• pp.383-388
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• 2011

Regulators of G-protein signaling (RGS) proteins are regulators of $Ca^{2+}$ signaling that accelerate the GTPase activity of the G-protein ${\alpha}$ -subunit. RGS1, RGS2, RGS4, and RGS16 are expressed in the pancreas, and RGS2 regulates G-protein coupled receptor (GPCR)-induced $Ca^{2+}$ oscillations. However, the role of RGS4 in $Ca^{2+}$ signaling in pancreatic acinar cells is unknown. In this study, we investigated the mechanism of GPCR-induced $Ca^{2+}$ signaling in pancreatic acinar cells derived from $RGS4^{-/-}$ mice. $RGS4^{-/-}$ acinar cells showed an enhanced stimulus intensity response to a muscarinic receptor agonist in pancreatic acinar cells. Moreover, deletion of RGS4 increased the frequency of $Ca^{2+}$ oscillations. $RGS4^{-/-}$ cells also showed increased expression of sarco/endoplasmic reticulum $Ca^{2+}$ ATPase type 2. However, there were no significant alterations, such as $Ca^{2+}$ signaling in treated high dose of agonist and its related amylase secretion activity, in acinar cells from $RGS4^{-/-}$ mice. These results indicate that RGS4 protein regulates $Ca^{2+}$ signaling in mouse pancreatic acinar cells.

• Journal of Microbiology
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• v.44 no.2
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• pp.145-154
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• 2006

Heterotrimeric G proteins (G proteins) are conserved in all eukaryotes and are crucial components sensing and relaying external cues into the cells to elicit appropriate physiological and biochemical responses. Basic units of the heterotrimeric G protein signaling system include a G protein-coupled receptor (GPCR), a G protein composed of ${\alpha},\;{\beta},\;and\;{\gamma}$ subunits, and variety of effectors. Sequential sensitization and activation of these G protein elements translates external signals into gene expression changes, resulting in appropriate cellular behaviors. Regulators of G protein signaling (RGSs) constitute a crucial element of appropriate control of the intensity and duration of G protein signaling. For the past decade, G protein signaling and its regulation have been intensively studied in a number of model and/or pathogenic fungi and outcomes of the studies provided better understanding on the upstream regulation of vegetative growth, mating, development, virulence/pathogenicity establishment, and biosynthesis of secondary metabolites in fungi. This review focuses on the characteristics of the basic upstream G protein components and RGS proteins, and their roles controlling various aspects of biological processes in the model filamentous ascomycete fungus Aspergillus nidulans. In particular, their functions in controlling hyphal proliferation, asexual spore formation, sexual fruiting, and the mycotoxin sterigmatocystin production are discussed.

• Journal of Life Science
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• v.19 no.11
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• pp.1506-1513
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• 2009

RGS proteins have been identified as negative regulators of G protein signalling pathways and attenuate the activity of GPCR receptors. However, information on the regulatory effects of RGS proteins in the activity of cannabinoid receptors is limited. In this study, the role of RGS proteins on the signal transduction of the CB2 cannabinoid receptor was investigated in HEK293 cells co-transfected with CB2-receptors and plasmids encoding RGS2, RGS3, RGS4 and RGS5. Treatment of cells with WIN55, 212-2, a CB2 receptor agonist, inhibited forskolin-induced cAMP response element (CRE) activity in CB2-transfected HEK293 (CB2-HEK293) cells. This inhibitory effect of WIN 55, 212-2 on CRE activity was reversed by co-transfection of CB2-HEK293 cells with RGS3, but not with RGS2, RGS4 and RGS5. However, endogenous RGS3 protein knocked down by a small interfering siRNA targeting RGS3 gene enhanced inhibition of forskolin induced CRE activity via agonist induced CB2 receptor signal transduction. These results indicate the functional role of endogenous RGS protein in cannabinoid signaling pathways and define receptor-selective roles of endogenous RGS3 in modulating CRE transcriptional responses to agonist induced CB2 receptor activity.

• BMB Reports
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• v.47 no.6
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• pp.324-329
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• 2014

Regulators of G-protein signaling (RGS) proteins regulate certain G-protein-coupled receptor (GPCR)-mediated signaling pathways. The GABAB receptor ($GABA_BR$) is a GPCR that plays a role in the stress response. Previous studies indicate that acute immobilization stress (AIS) decreases RGS4 in the prefrontal cortex (PFC) and hypothalamus (HY) and suggest the possibility of a signal complex composed of RGS4 and $GABA_BR$. Therefore, in the present study, we tested whether RGS4 associates with $GABA_BR$ in these brain regions. We found the co-localization of RGS4 and $GABA_BR$ subtypes in the PFC and HY using double immunohistochemistry and confirmed a direct association between $GABA_{B2}R$ and RGS4 proteins using co-immunoprecipitation. Furthermore, we found that AIS decreased the amount of RGS4 bound to $GABA_{B2}R$ and the number of double-positive cells. These results indicate that $GABA_BR$ forms a signal complex with RGS4 and suggests that RGS4 is a regulator of $GABA_BR$.

• Proceedings of the Ginseng society Conference
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• 2002.10a
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• pp.66-83
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• 2002

Recently, we have provided evidence that ginsenosides, the active components of Panax ginseng, utilize pertussis toxin (PTX)-insensitive $G{\alpha}_{q/11}-phospholipase\;C-{\beta}3(PLC-{\beta}3)$ signal transduction pathway for the enhancement of $Ca^{2+}-activated\;Cl^{-}$ current in the Xenopus oocyte (British J. Pharmacol. 132, 641-647, 2001; JBC 276, 48797-48802, 2001). Other investigators have shown that stimulation of receptors linked to $G{\alpha}-PLC$ pathway inhibits the activity of G proteincoupled inwardly rectifying $K^+$ (GIRK) channel. In the present study, we sought to determine whether ginsenosides influenced the activity of GIRK 1 and GIRK 4 (GIRK 1/4) channels expressed in the Xenopus oocyte, and if so, the underlying signal transduction mechanism. In oocyte injected with GIRK 1/4 channel cRNAs, bath-applied ginsenosides inhibited high potassium (HK) solution-elicited GIRK current $(EC_{50}:4.9{\pm}4.3\;{\mu}g/ml).$ Pretreatment of the oocyte with PTX reduced the HK solution-elicited GIRK current by $49\%,$ but it did not alter the inhibitory ginsenoside effect on GIRK current. Prior intraoocyte injection of cRNA(s) coding $G{\alpha}_q,\;G{\alpha}_{11}\;or\;G{\alpha}_q/G{\alpha}_{11},\;but\;not\;G{\alpha}_{i2}\;or\;G{\alpha}_{oA}$ attenuated the inhibitory ginsenoside effect. Injection of cRNAs coding $G{\beta}_{1{\gamma}2}$ also attenuated the ginsenoside effect. Similarly, injection of the cRNAs coding regulators of G protein signaling 1, 2 and 4 (RGS1, RGS2 and RGS4), which interact with $G{\alpha}_i\;and/or\;G{\alpha}_{q/11}$ and stimulates the hydrolysis of GTP to GDP in active GTP-bound $G{\alpha}$ subunit, resulted in a significant reduction of ginsenoside effect on GIRK current. Preincubation of GIRK channel-expressing oocyte in PLC inhibitor (U73122) or protein kinase C (PKC) inhibitor (staurosporine or chelerythrine) blocked the inhibitory ginsenoside effect on GIRK current. On the other hand, intraoocyte injection of BAPTA, a free $Ca^{2+}$ chelator, had no significant effect on the ginsenoside action. Taken together, these results suggest that ginsenosides inhibit the activity of GIRK 1/4 channel expressed in the Xenopus oocyte through a PTX-insensitive and $G{\alpha}_{q/11}$-,PLC-and PKC-mediated signal transduction pathway.