Class A Orphans (version 2020.5) in the IUPHAR/BPS Guide to Pharmacology Database

Alexander, Stephen P.H.; Battey, Jim; Benson, Helen E.; Benya, Richard V.; Bonner, Tom I.; Davenport, Anthony P.; Singh, Khuraijam Dhanachandra; Eguchi, Satoru; Harmar, Anthony J.; Holliday, Nicholas D.; Jensen, Robert T.; Karnik, Sadashiva S.; Kostenis, Evi; Liew, Wen Chiy; Monaghan, Amy E.; Mpamhanga, Chido; Neubig, Richard; Pawson, Adam J.; Pin, Jean‐Philippe; Sharman, Joanna L.; Spedding, Michael; Spindel, Eliot R.; Stoddart, Leigh A.; Storjohann, Laura; Thomas, Walter G.; Tirupula, Kalyan; Vanderheyden, Patrick

doi:10.2218/gtopdb/f16/2020.5

Cited by 10 publications

(9 citation statements)

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“… ,, Their potencies can vary from a few to one hundred micromolar range in various assay platforms (Table ). Thus, MCFAs have been proposed to be the endogenous ligands of GPR84, but GPR84 has not been officially deorphanized as a free fatty acid receptor because the concentration of MCFA under physiological conditions is only around its EC 50 for GPR84 activation and is greatly affected by diets. Analysis of fasting blood of healthy adult volunteers ( n = 43) showed that C10 concentration is between 2 and 18 μM, and dodecanoic acid ( C12 ) concentration is between 6 and 90 μM .…”

Section: Agonistsmentioning

confidence: 99%

Modulation of the G-Protein-Coupled Receptor 84 (GPR84) by Agonists and Antagonists

2020

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Since the discovery of medium-chain fatty acids as GPR84 ligands, significant advancements have been made in the development of GPR84 agonists and antagonists. Most agonists have lipid-like structures except for 3,3′-diindolylmethane (DIM), which acts as an allosteric agonist. GPR84 activation in macrophages leads to increased cytokine secretion, chemotaxis, and phagocytosis, revealing the proinflammatory role of GPR84 associated with various inflammatory responses. Three GPR84 antagonists (S)-2-((1,4-dioxan-2-yl)methoxy)-9-(cyclopropylethynyl)-6,7-dihydro-4H-pyrimido[6,1-a]isoquinolin-4-one (GLPG1205), sodium 2-(3-pentylphenyl)acetate (PBI-4050), and sodium 2-(3,5-dipentylphenyl)acetate (PBI-4547) have displayed therapeutic effects in animal models of several inflammatory and fibrotic diseases and are being evaluated in clinical studies. Although GLPG1205 has failed in a clinical trial for ulcerative colitis, it is undergoing another phase II clinical study for idiopathic pulmonary fibrosis. Further studies are needed to resolve the GPR84 structure, identify more endogenous ligands, elucidate their physiological and pathological roles, and fulfill the therapeutic potential of GPR84 antagonists and agonists.

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Section: Agonistsmentioning

confidence: 99%

Modulation of the G-Protein-Coupled Receptor 84 (GPR84) by Agonists and Antagonists

2020

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“…Additionally, evidence of ligand binding in a given tissue via in vitro binding assays, functional assays, and anatomic data is crucial [ 58 ]. For MRGPR, at least one of the criteria mentioned is lacking; however, in a recent report in 2019 by IUPHAR/BPS, MRGPRX2 is listed as a class A orphan GPCR for which preliminary evidence for an endogenous ligand and potential disease link has been published [ 65 ].…”

Section: Pharmacology Of Mas-related G Protein-coupled Receptors X 2 (Mrgprx2)mentioning

confidence: 99%

Unlocking the Non-IgE-Mediated Pseudo-Allergic Reaction Puzzle with Mas-Related G-Protein Coupled Receptor Member X2 (MRGPRX2)

Kumar

Duraisamy

Chow

2021

Cells

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Mas-related G-protein coupled receptor member X2 (MRGPRX2) is a class A GPCR expressed on mast cells. Mast cells are granulated tissue-resident cells known for host cell response, allergic response, and vascular homeostasis. Immunoglobulin E receptor (FcεRI)-mediated mast cell activation is a well-studied and recognized mechanism of allergy and hypersensitivity reactions. However, non-IgE-mediated mast cell activation is less explored and is not well recognized. After decades of uncertainty, MRGPRX2 was discovered as the receptor responsible for non-IgE-mediated mast cells activation. The puzzle of non-IgE-mediated pseudo-allergic reaction is unlocked by MRGPRX2, evidenced by a plethora of reported endogenous and exogenous MRGPRX2 agonists. MRGPRX2 is exclusively expressed on mast cells and exhibits varying affinity for many molecules such as antimicrobial host defense peptides, neuropeptides, and even US Food and Drug Administration-approved drugs. The discovery of MRGPRX2 has changed our understanding of mast cell biology and filled the missing link of the underlying mechanism of drug-induced MC degranulation and pseudo-allergic reactions. These non-canonical characteristics render MRGPRX2 an intriguing player in allergic diseases. In the present article, we reviewed the emerging role of MRGPRX2 as a non-IgE-mediated mechanism of mast cell activation in pseudo-allergic reactions. We have presented an overview of mast cells, their receptors, structural insight into MRGPRX2, MRGPRX2 agonists and antagonists, the crucial role of MRGPRX2 in pseudo-allergic reactions, current challenges, and the future research direction.

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“…Characterization of orphan receptors may lead to uncovering physiological functions, thus connecting them to diseases. GPR39 is among the class A orphan receptors [2]. Several endogenous agonists have been proposed, including the element zinc [3,4], yet the classification of GPR39 as a zinc receptor remains contentious.…”

Section: Introductionmentioning

confidence: 99%

Alterations of Serum Magnesium Concentration in Animal Models of Seizures and Epilepsy—The Effects of Treatment with a GPR39 Agonist and Knockout of the Gpr39 Gene

Doboszewska

Sawicki

Sajnóg

et al. 2022

Cells

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Several ligands have been proposed for the GPR39 receptor, including the element zinc. The relationship between GPR39 and magnesium homeostasis has not yet been examined, nor has such a relationship in the context of seizures/epilepsy. We used samples from mice that were treated with an agonist of the GPR39 receptor (TC-G 1008) and underwent acute seizures (maximal electroshock (MES)- or 6-hertz-induced seizures) or a pentylenetetrazole (PTZ)-induced kindling model of epilepsy. MES seizures and PTZ kindling, unlike 6 Hz seizures, increased serum magnesium concentration. In turn, Gpr39-KO mice that underwent PTZ kindling displayed decreased concentrations of this element compared to WT mice subjected to this procedure. However, the levels of expression of TRPM7 and SlC41A1 proteins—which are responsible for magnesium transport into and out of cells, respectively—did not differ in the hippocampus between Gpr39-KO and WT mice. Furthermore, laser ablation inductively coupled plasma mass spectrometry applied to hippocampal slices did not reveal differences in magnesium levels between the groups. These data show the relationship between magnesium homeostasis and certain types of acute or chronic seizures (MES seizures or PTZ kindling, respectively), but do not explicitly support the role of GPR39 in mediating magnesium balance in the hippocampus in the latter model. However, decreased expression of TRPM7 and increased expression of SLC41A1—which were observed in the hippocampi of Gpr39-KO mice treated with TC-G 1008, in comparison to WT mice that received the same treatment—implicitly support the link between GPR39 and hippocampal magnesium homeostasis.

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Class A Orphans (version 2020.5) in the IUPHAR/BPS Guide to Pharmacology Database

Cited by 10 publications

References 0 publications

Modulation of the G-Protein-Coupled Receptor 84 (GPR84) by Agonists and Antagonists

Modulation of the G-Protein-Coupled Receptor 84 (GPR84) by Agonists and Antagonists

Unlocking the Non-IgE-Mediated Pseudo-Allergic Reaction Puzzle with Mas-Related G-Protein Coupled Receptor Member X2 (MRGPRX2)

Alterations of Serum Magnesium Concentration in Animal Models of Seizures and Epilepsy—The Effects of Treatment with a GPR39 Agonist and Knockout of the Gpr39 Gene

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