The Roles of Orphan G Protein-Coupled Receptors in Autoimmune Diseases

Zhao, Mingming; Wang, Zheyu; Yang, Ming; Ding, Yan; Zhao, Ming; Wu, Haijing; Zhang, Yan; Lu, Qianjin

doi:10.1007/s12016-020-08829-y

Cited by 9 publications

(2 citation statements)

References 189 publications

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“…The array of established GPCR ligands is as wide-ranging and rich as the physiological processes that they mediate, and these include odorants, gustatory molecules, ions, photons, protons, neurotransmitters, hormones, chemokines, lipids, pheromones, amino acids and their derivatives, peptides, nucleotides, small organic molecules (Bockaert, 1999;Civelli, 2001;Kroeze et al, 2003;Civelli et al, 2006) and microbial products such as short chain fatty acids and signal peptides (Brown et al, 2003). Despite the broad scope of GPCRs mediating physiological processes and their therapeutic relevance in OPEN ACCESS EDITED BY cancer, metabolic disorders, autoimmune diseases, and central nervous system (CNS) disorders, some remain as orphans for which no endogenous ligand(s) have been identified (Zhao et al, 2021). Orphan GPCRs account for ~30% of the ~400 non-olfactory human GPCRs (Laschet et al, 2018;Alexander et al, 2019) as illustrated in Figure 1.…”

Section: Introductionmentioning

confidence: 99%

“…Orphan GPCRs account for ~30% of the ~400 non-olfactory human GPCRs (Laschet et al, 2018;Alexander et al, 2019) as illustrated in Figure 1. The "non-sensory" GPCRs are targeted by over 40% of clinically administered drugs (Zhao et al, 2021). In a joint effort between the British Pharmacological Society and the International Union of Basic and Clinical Pharmacology (IUPHAR), a record of orphans and the extensive set of deorphanized GPCRs (Alexander et al, 2019) is archived in the Guide to Pharmacology database accessible at https:// www.guidetopharmacology.org/GRAC/ReceptorFamiliesForward?type= GPCR.…”

Section: Introductionmentioning

confidence: 99%

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Orphan G protein-coupled receptors: the ongoing search for a home

Jobe,

Vijayan

2024

Front. Pharmacol.

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G protein-coupled receptors (GPCRs) make up the largest receptor superfamily, accounting for 4% of protein-coding genes. Despite the prevalence of such transmembrane receptors, a significant number remain orphans, lacking identified endogenous ligands. Since their conception, the reverse pharmacology approach has been used to characterize such receptors. However, the multifaceted and nuanced nature of GPCR signaling poses a great challenge to their pharmacological elucidation. Considering their therapeutic relevance, the search for native orphan GPCR ligands continues. Despite limited structural input in terms of 3D crystallized structures, with advances in machine-learning approaches, there has been great progress with respect to accurate ligand prediction. Though such an approach proves valuable given that ligand scarcity is the greatest hurdle to orphan GPCR deorphanization, the future pairings of the remaining orphan GPCRs may not necessarily take a one-size-fits-all approach but should be more comprehensive in accounting for numerous nuanced possibilities to cover the full spectrum of GPCR signaling.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Orphan G protein-coupled receptors: the ongoing search for a home

Jobe,

Vijayan

2024

Front. Pharmacol.

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The GPR35 expression pattern is associated with overall survival in male patients with colorectal cancer

et al. 2022

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The orphan G protein–coupled receptor 141 expressed in myeloid cells functions as an inflammation suppressor

Sawabe,

Okazaki,

Nakamura

et al. 2024

Journal of Leukocyte Biology

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G protein-coupled receptors (GPCRs) regulate many cellular processes in response to various stimuli, including light, hormones, neurotransmitters, and odorants, some of which play critical roles in innate and adaptive immune responses. However, the physiological functions of many GPCRs and the involvement of them in autoimmune diseases of the central nervous system remain unclear. Here, we demonstrate that GPR141, an orphan GPCR belonging to the class A receptor family, suppresses immune responses. High GPR141 mRNA levels were expressed in myeloid-lineage cells, including neutrophils (CD11b + Gr1+), monocytes (CD11b + Gr1-Ly6C+ and CD11b + Gr1-Ly6C-), macrophages (F4/80+), and dendritic cells (DCs) (CD11c+). Gpr141−/- mice, that we independently generated, displayed almost no abnormalities in myeloid cell differentiation and compartmentalization in the spleen and bone marrow under steady-state conditions. However, Gpr141 deficiency exacerbated disease conditions of experimental autoimmune encephalomyelitis (EAE), an autoimmune disease model for multiple sclerosis, with increased inflammation in the spinal cord. Gpr141−/- mice showed increased CD11b + Gr1+ neutrophils, CD11b + Gr1- monocytes, CD11c+ DC, and CD4+ T cell infiltration into the EAE–induced spinal cord compared to littermate control mice. Lymphocytes enriched from Gpr141−/- mice immunized with myelin oligodendrocyte glycoprotein (MOG)35-55 produced high amounts of interferon-γ, interleukin (IL)-17A, and IL-6 compared to those from WT mice. Moreover, CD11c+ DCs purified from Gpr141−/- mice increased cytokine production of MOG35-55 specific T cells. These findings suggest that GPR141 functions as a negative regulator of immune responses by controlling the functions of monocytes and DCs and that targeting GPR141 may be a possible therapeutic intervention for modulating chronic inflammatory diseases.

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The Roles of Orphan G Protein-Coupled Receptors in Autoimmune Diseases

Cited by 9 publications

References 189 publications

Orphan G protein-coupled receptors: the ongoing search for a home

Orphan G protein-coupled receptors: the ongoing search for a home

The GPR35 expression pattern is associated with overall survival in male patients with colorectal cancer

The orphan G protein–coupled receptor 141 expressed in myeloid cells functions as an inflammation suppressor

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