GPR75

Official Full Name

G protein-coupled receptor 75

Organism

Homo sapiens

GeneID

10936

Background

GPR75 is a member of the G protein-coupled receptor family. GPRs are cell surface receptors that activate guanine-nucleotide binding proteins upon the binding of a ligand.[supplied by OMIM, Jul 2002]

Synonyms

GPRchr2; WI31133;

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Detailed Information

The GPR75 gene encodes G protein-coupled receptor 75 (GPR75), a relatively unique member of the class A rhodopsin-like GPCR family. Although its endogenous ligand remained elusive for a long time, recent studies have identified CCL5 (RANTES) as a functional ligand for GPR75. CCL5 is a chemokine widely involved in inflammation and immune regulation. Structurally, GPR75 exhibits the typical seven-transmembrane topology of GPCRs, and its signaling is primarily Gq protein-coupled, activating phospholipase C, generating inositol triphosphate, and inducing intracellular calcium release-a hallmark of Gq signaling. GPR75 is expressed in a tissue-specific manner, with relatively high levels in the central nervous system and pancreas, providing important clues to its biological functions.

Biological Significance

The biological role of GPR75 is becoming clearer following the identification of its ligand, revealing pleiotropic regulatory functions in the nervous and metabolic systems. In the central nervous system, the GPR75-CCL5 axis may promote neuronal survival. Activation of GPR75 by CCL5 triggers downstream signaling pathways involving phosphoinositide 3-kinase (PI3K), Akt, and MAPK, which are central to cell survival and proliferation, suggesting a neuroprotective role against injury or neurodegenerative stress. This finding highlights a non-inflammatory role of chemokines in neural regulation.

In metabolic regulation, GPR75 expression in pancreatic islet cells suggests involvement in glucose homeostasis. CCL5-mediated activation of GPR75 has been shown to influence insulin secretion from β-cells, implying a novel immunometabolic communication axis. Notably, large-scale human genetic studies have demonstrated that loss-of-function variants of GPR75 are strongly associated with lower body mass index and markedly reduced obesity risk, with carriers of rare heterozygous mutations exhibiting more than 50% reduction in obesity risk. This compelling evidence positions GPR75 as a key regulator of energy balance and body weight, likely promoting energy-positive balance under normal conditions. Mechanistic details may involve central appetite regulation, energy expenditure modulation, or direct effects on adipose tissue function.

Figure 1. GPR75 signaling pathways that influence cancer proliferation. (Ghorbanzadeh F, et al., 2023)

Clinical Relevance

GPR75 has significant clinical translational potential, particularly as a therapeutic target for obesity. Genetic evidence supports GPR75 as one of the most compelling anti-obesity drug targets. Selective GPR75 antagonists could mimic protective loss-of-function variants, reducing body weight safely and effectively. Compared with current drugs targeting other appetite pathways (e.g., GLP-1 receptor agonists), GPR75-targeted therapies may act via a novel mechanism, providing options for patients resistant to existing treatments. Given the global obesity epidemic and its associated complications (type 2 diabetes, cardiovascular disease), GPR75-focused drug development has attracted considerable interest.

Beyond metabolic disease, GPR75 may also play roles in chronic inflammatory conditions, atherosclerosis, and tumor microenvironments, owing to its ligand CCL5's involvement in inflammation and chemotaxis. However, research in these areas remains early-stage, and the therapeutic significance requires further investigation. Clinical development of GPR75 antagonists for obesity faces challenges, including defining the downstream signaling pathways and target cells (central nervous system vs. peripheral organs such as adipose tissue and liver) and assessing long-term safety, particularly regarding its neuroprotective and insulin-regulatory roles. Nonetheless, GPR75 represents a promising novel target for combating obesity, offering new hope and direction in metabolic disease therapy.

References

Akbari P, Tuncman G, Schuurman AS, et al. Sequencing of 640,000 exomes identifies GPR75 variants associated with protection from obesity. Science. 2021;373(6550):eabf8683.
Wang S, Gao S, Wang F. Effect and mechanism of GPR75 in metabolic dysfunction-related steatosis liver disease. Int J Med Sci. 2024 Sep 9;21(12):2343-2347.
Ghorbanzadeh F, Jafari-Gharabaghlou D, Dashti MR, et al. Advanced nano-therapeutic delivery of metformin: potential anti-cancer effect against human colon cancer cells through inhibition of GPR75 expression. Med Oncol. 2023 Jul 29;40(9):255.

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