A Physiologically Required G Protein-coupled Receptor (GPCR)-Regulator of G Protein Signaling (RGS) Interaction That Compartmentalizes RGS Activity

Croft, Wayne; Hill, Claire; Bond, Michael; Esparza-Franco, Manuel A.; Bennett, Jeannette; Rand, D.A.J.; Davey, John; Ladds, Graham

doi:10.1074/jbc.m113.497826

Cited by 17 publications

(25 citation statements)

References 62 publications

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“…Despite common localization of interacting partners in the plasma membrane, many RGS proteins have been detected in the cytoplasm and nucleus [38,39]. Membrane localization of RGS proteins is attributable to G protein and GPCR activation [40][41][42], protein structures [43][44][45], and interactions with scaffolding proteins [46][47][48].…”

Section: Discussionmentioning

confidence: 99%

The regulators of G protein signaling RGS16 and RGS18 inhibit protease‐activated receptor 2/Gi/o signaling through distinct interactions with Gα in live cells

2018

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Protease-activated receptor 2 (PAR2) is a G protein-coupled receptor (GPCR) activated by endogenous proteases, in particular, trypsin. Although regulators of G protein signaling (RGS) are known to inhibit GPCR/Gα-mediated signaling, their specific effects on PAR2 are poorly understood at present. Here, we use a bioluminescence resonance energy transfer technique to investigate whether RGS16 and RGS18 bind PAR2 in live cells to regulate PAR2/Gα -mediated signaling. Notably, we find that RGS16 binds to PAR2 in the presence of Gα while RGS18 does not interact with PAR2, regardless of the presence of Gα. Both RGS16 and RGS18 inhibit PAR2/Gα -mediated signaling. To our knowledge, the current study is the first to highlight the effects of RGS proteins on PAR2-mediated signaling.

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Section: Discussionmentioning

confidence: 99%

The regulators of G protein signaling RGS16 and RGS18 inhibit protease‐activated receptor 2/Gi/o signaling through distinct interactions with Gα in live cells

2018

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“…Rgs1 is a GTPase-activating protein for the receptor-coupled Gα Gpa1 previously characterized for its role in desensitization (Watson et al 1999;Pereira and Jones 2001;Croft et al 2013). In this mutant, which mounts an exaggerated pheromone response, the Map3 receptor was not enriched at the fusion focus in both autocrine M cells and P cells engaged in cell pairs (Fig.…”

Section: Loss Of Pheromone Receptor Focalization Correlates With Fusimentioning

confidence: 91%

Spatial focalization of pheromone/MAPK signaling triggers commitment to cell–cell fusion

2016

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Cell fusion is universal in eukaryotes for fertilization and development, but what signals this process is unknown. Here, we show in Schizosaccharomyces pombe that fusion does not require a dedicated signal but is triggered by spatial focalization of the same pheromone-GPCR (G-protein-coupled receptor)-MAPK signaling cascade that drives earlier mating events. Autocrine cells expressing the receptor for their own pheromone trigger fusion attempts independently of cell-cell contact by concentrating pheromone release at the fusion focus, a dynamic actin aster underlying the secretion of cell wall hydrolases. Pheromone receptor and MAPK cascade are similarly enriched at the fusion focus, concomitant with fusion commitment in wild-type mating pairs. This focalization promotes cell fusion by immobilizing the fusion focus, thus driving local cell wall dissolution. We propose that fusion commitment is imposed by a local increase in MAPK concentration at the fusion focus, driven by a positive feedback between fusion focus formation and focalization of pheromone release and perception.

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“…Recent studies indicate that GPCRs interact with RGS proteins, such as M2R/RGS4, M1 muscarinic receptor/RGS2 and β2 adrenergic receptors/RGS2 (Abramow-Newerly et al 2006;Jaén & Doupnik, 2006). The coupling of receptors and RGS proteins regulates the affinity of RGS proteins for their G-protein targets and the selectivity of RGS activity at the plasma membrane (Abramow-Newerly et al 2006;Jaén & Doupnik, 2006;Croft et al 2013). Therefore, the agonist-M2R complex may not only alter their interaction with RGS4 but also directly or indirectly influence the RGS4-Gα association in a ligand-dependent manner.…”

Section: Discussionmentioning

confidence: 99%

RGS4 regulates partial agonism of the M2 muscarinic receptor‐activated K⁺ currents

Chen¹,

Furutani

Inanobe

et al. 2014

The Journal of Physiology

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Partial agonists are used clinically to avoid overstimulation of receptor-mediated signalling, as they produce a submaximal response even at 100% receptor occupancy. The submaximal efficacy of partial agonists is due to conformational change of the agonist–receptor complex, which reduces effector activation. In addition to signalling activators, several regulators help control intracellular signal transductions. However, it remains unclear whether these signalling regulators contribute to partial agonism. Here we show that regulator of G-protein signalling (RGS) 4 is a determinant for partial agonism of the M2 muscarinic receptor (M2R). In rat atrial myocytes, pilocarpine evoked smaller G-protein-gated K+ inwardly rectifying (KG) currents than those evoked by ACh. In a Xenopus oocyte expression system, pilocarpine acted as a partial agonist in the presence of RGS4 as it did in atrial myocytes, while it acted like a full agonist in the absence of RGS4. Functional couplings within the agonist–receptor complex/G-protein/RGS4 system controlled the efficacy of pilocarpine relative to ACh. The pilocarpine–M2R complex suppressed G-protein-mediated activation of KG currents via RGS4. Our results demonstrate that partial agonism of M2R is regulated by the RGS4-mediated inhibition of G-protein signalling. This finding helps us to understand the molecular components and mechanism underlying the partial agonism of M2R-mediated physiological responses.

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A Physiologically Required G Protein-coupled Receptor (GPCR)-Regulator of G Protein Signaling (RGS) Interaction That Compartmentalizes RGS Activity

Cited by 17 publications

References 62 publications

The regulators of G protein signaling RGS16 and RGS18 inhibit protease‐activated receptor 2/Gi/o signaling through distinct interactions with Gα in live cells

The regulators of G protein signaling RGS16 and RGS18 inhibit protease‐activated receptor 2/Gi/o signaling through distinct interactions with Gα in live cells

Spatial focalization of pheromone/MAPK signaling triggers commitment to cell–cell fusion

RGS4 regulates partial agonism of the M2 muscarinic receptor‐activated K⁺ currents

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A Physiologically Required G Protein-coupled Receptor (GPCR)-Regulator of G Protein Signaling (RGS) Interaction That Compartmentalizes RGS Activity

Cited by 17 publications

References 62 publications

The regulators of G protein signaling RGS16 and RGS18 inhibit protease‐activated receptor 2/Gi/o signaling through distinct interactions with Gα in live cells

The regulators of G protein signaling RGS16 and RGS18 inhibit protease‐activated receptor 2/Gi/o signaling through distinct interactions with Gα in live cells

Spatial focalization of pheromone/MAPK signaling triggers commitment to cell–cell fusion

RGS4 regulates partial agonism of the M2 muscarinic receptor‐activated K+ currents

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RGS4 regulates partial agonism of the M2 muscarinic receptor‐activated K⁺ currents