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GPR39: An orphan receptor begging for ligands
Urszula Doboszewska1, Wolfgang Maret2, Piotr Wlaź3
1Department of Pharmacobiology, Jagiellonian University Medical College, Medyczna 9, PL 30-688 Kraków, Poland.
Drug Discovery Today
|December 20, 2023
Summary
Pharmacological data for the G protein-coupled receptor 39 (GPR39) are inconsistent, hindering progress. This review critically assesses ligand identification, synthetic agonist specificity, and therapeutic strategies for GPR39 signaling.
Area of Science:
- Pharmacology
- Molecular Biology
- Biochemistry
Background:
- The G protein-coupled receptor 39 (GPR39) is a target of therapeutic interest, but its understanding is impeded by conflicting pharmacological data.
- Key areas of debate include the identity of endogenous ligands (e.g., zinc ions, eicosanoids) and the specificity of synthetic agonists like TC-G 1008.
Purpose of the Study:
- To critically scrutinize existing data on GPR39 signaling and functions.
- To identify factors contributing to divergent experimental outcomes and interpretations regarding GPR39.
- To evaluate the therapeutic potential of GPR39 modulation, considering both activation and inhibition.
Main Methods:
- Comprehensive literature review of pharmacological and functional studies on GPR39.
- Critical analysis of data concerning endogenous and synthetic ligands.
- Assessment of evidence for constitutive activity and biased agonism/antagonism.
Main Results:
- Inconsistent findings regarding GPR39's endogenous ligands (zinc ions, eicosanoids) and synthetic agonist (TC-G 1008) specificity complicate its study.
- Emerging evidence suggests that GPR39 inhibition may be beneficial in certain disease contexts, challenging solely activation-based therapeutic strategies.
- The receptor exhibits constitutive activity and promiscuous signaling, necessitating the development of antagonists/inverse agonists alongside biased agonists.
Conclusions:
- Resolving inconsistencies in GPR39 pharmacology is crucial for advancing its therapeutic applications.
- A nuanced understanding of GPR39's dual role (activation vs. inhibition) and signaling properties is required for effective drug development.
- Future research should focus on clarifying ligand identity, receptor specificity, and the therapeutic utility of GPR39 modulators.
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