Key result
GPR3 emerges as a central signaling hub and potential therapeutic target for chronic multisystem disorders.
Why the study?
GPR3 shows potential as a therapeutic target for chronic multisystem disorders, but its dual roles in certain pathologies and translation challenges necessitate further research.
GPR3 serves as a central molecular hub across multiple physiological systems, presenting a potential therapeutic target for chronic multisystem disorders.
Hypothesis-generating for GPR3 as a multisystem target; prospective studies needed before clinical consideration.
BACKGROUND: GPR3(G-protein-coupled receptor 3), an orphan G-protein-coupled receptor (GPCR) with constitutive Gs activity, is expressed in the brain, liver, ovary, and other tissues, regulating cell proliferation, differentiation, and apoptosis across the nervous, reproductive, immune, and metabolic systems. This review synthesizes evidence on its integrated signaling and physiological functions to address the lack of a comprehensive multisystem pathophysiology overview. METHODS: A systematic literature search was conducted on PubMed and Web of Science, using keywords such as "GPR3", "GPCR", "neurodegeneration", "metabolism", "immune", "reproduction", "agonist", "inhibitor", and "therapeutic target". This search identified GPR3's roles in neurodegenerative diseases, immune inflammation, reproduction, and energy metabolism. The analysis focused on signaling pathways, ligand regulation, and therapeutic potential. RESULTS: the cAMP/PKA, PI3K/Akt, and β - arrestin pathways. It promotes amyloid - β formation in Alzheimer's disease (AD), yet provides neuroprotection in Parkinson's disease (PD) models. It may contribute to anxiety/depression - like states, maintain oocyte meiotic arrest in the ovary, and activate thermogenic genes in adipose tissue. GPR3 modulates immune responses. Using oleic acid (OA) and diphenyleneiodonium (DPI) as activators, and AF64394 and cannabidiol (CBD) as antagonists, it shows potential in disease models. CONCLUSION: GPR3 acts as a central molecular hub integrating neural, metabolic, immune, and reproductive signaling, highlighting its potential as a therapeutic target for chronic multisystem disorders. However, its dual roles in certain pathologies and translation challenges necessitate further research.
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Feng et al. (2026) conducted a review in Multi-System diseases. GPR3 was evaluated. GPR3 acts as a central molecular hub integrating neural, metabolic, immune, and reproductive signaling, highlighting its potential as a therapeutic target for chronic multisystem disorders.
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