Functional interaction of regulator of G protein signaling‐2 with melanin‐concentrating hormone receptor 1

Miyamoto-Matsubara, Mayumi; Chung, Shinjae; Saito, Yumiko

doi:10.1111/j.1749-6632.2010.05507.x

Cited by 6 publications

(3 citation statements)

References 33 publications

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“…RGS5 may also have differential efficacy toward certain G protein-receptor combinations. Although most of the RGS proteins in the R4 subfamily bind G␣ i and G␣ q family members promiscuously, there is substantial evidence for direct interactions with GPCRs (44,45), which may specify selectivity for certain receptor-G protein combinations. A previous study found that chemotaxis of neutrophils elicited by fMLP, but not chemokines, is partially dependent on G␣ q (46).…”

Section: Rgs5 and Neutrophil Migrationmentioning

confidence: 99%

Regulator of G protein signaling 5 restricts neutrophil chemotaxis and trafficking

Chan

Ren

Jude

et al. 2018

Journal of Biological Chemistry

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Neutrophils are white blood cells that are mobilized to damaged tissues and to sites of pathogen invasion, providing the first line of host defense. Chemokines displayed on the surface of blood vessels promote migration of neutrophils to these sites, and tissue- and pathogen-derived chemoattractant signals, including -formylmethionylleucylphenylalanine (fMLP), elicit further migration to sites of infection. Although nearly all chemoattractant receptors use heterotrimeric G proteins to transmit signals, many of the mechanisms lying downstream of chemoattractant receptors that either promote or limit neutrophil motility are incompletely defined. Here, we show that regulator of G protein signaling 5 (RGS5), a protein that modulates G protein activity, is expressed in both human and murine neutrophils. We detected significantly more neutrophils in the airways of mice than WT counterparts following acute respiratory virus infection and in the peritoneum in response to injection of thioglycollate, a biochemical proinflammatory stimulus. RGS5-deficient neutrophils responded with increased chemotaxis elicited by the chemokines CC motif chemokine ligand 1 (CXCL1), CXCL2, and CXCL12 but not fMLP. Moreover, adhesion of these cells was increased in the presence of both CXCL2 and fMLP. In summary, our results indicate that RGS5 deficiency increases chemotaxis and adhesion, leading to more efficient neutrophil mobilization to inflamed tissues in mice. These findings suggest that RGS5 expression and activity in neutrophils determine their migrational patterns in the complex microenvironments characteristic of inflamed tissues.

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Section: Rgs5 and Neutrophil Migrationmentioning

confidence: 99%

Regulator of G protein signaling 5 restricts neutrophil chemotaxis and trafficking

Chan

Ren

Jude

et al. 2018

Journal of Biological Chemistry

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“…MCH-1R is widely distributed in the central nervous system and is particularly concentrated in regions that are involved in rewarding behavior, feeding behavior, and metabolic regulation . The distribution of the MCH-2R receptor is less clear . Behavior studies have demonstrated a physiological role of the MCH system in regulating food intake .…”

Section: Introductionmentioning

confidence: 99%

“…2 The distribution of the MCH-2R receptor is less clear. 8 Behavior studies have demonstrated a physiological role of the MCH system in regulating food intake. 4 Acute central administration of MCH or MCH-1R synthetic agonists leads to a rapid and significant increase in food intake in rodents.…”

Section: Introductionmentioning

confidence: 99%

Fighting Obesity with a Sugar-Based Library: Discovery of Novel MCH-1R Antagonists by a New Computational–VAST Approach for Exploration of GPCR Binding Sites

Heifetz

Barker

Verquin

et al. 2013

J. Chem. Inf. Model.

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Obesity is an increasingly common disease. While antagonism of the melanin-concentrating hormone-1 receptor (MCH-1R) has been widely reported as a promising therapeutic avenue for obesity treatment, no MCH-1R antagonists have reached the market. Discovery and optimization of new chemical matter targeting MCH-1R is hindered by reduced HTS success rates and a lack of structural information about the MCH-1R binding site. X-ray crystallography and NMR, the major experimental sources of structural information, are very slow processes for membrane proteins and are not currently feasible for every GPCR or GPCR-ligand complex. This situation significantly limits the ability of these methods to impact the drug discovery process for GPCR targets in "real-time", and hence, there is an urgent need for other practical and cost-efficient alternatives. We present here a conceptually pioneering approach that integrates GPCR modeling with design, synthesis, and screening of a diverse library of sugar-based compounds from the VAST technology (versatile assembly on stable templates) to provide structural insights on the MCH-1R binding site. This approach creates a cost-efficient new avenue for structure-based drug discovery (SBDD) against GPCR targets. In our work, a primary VAST hit was used to construct a high-quality MCH-1R model. Following model validation, a structure-based virtual screen yielded a 14% hit rate and 10 novel chemotypes of potent MCH-1R antagonists, including EOAI3367472 (IC50 = 131 nM) and EOAI3367474 (IC50 = 213 nM).

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RGS2 and RGS4 modulate melatonin-induced potentiation of glycine currents in rat retinal ganglion cells

Zhao

Dong

et al. 2011

Brain Research

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Functional interaction of regulator of G protein signaling‐2 with melanin‐concentrating hormone receptor 1

Cited by 6 publications

References 33 publications

Regulator of G protein signaling 5 restricts neutrophil chemotaxis and trafficking

Regulator of G protein signaling 5 restricts neutrophil chemotaxis and trafficking

Fighting Obesity with a Sugar-Based Library: Discovery of Novel MCH-1R Antagonists by a New Computational–VAST Approach for Exploration of GPCR Binding Sites

RGS2 and RGS4 modulate melatonin-induced potentiation of glycine currents in rat retinal ganglion cells

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