2. Academic Validation
  3. GPR88 impairs the signaling of kappa opioid receptors in a heterologous system and in primary striatal neurons

GPR88 impairs the signaling of kappa opioid receptors in a heterologous system and in primary striatal neurons

  • Neuropharmacology. 2025 Mar 1:265:110242. doi: 10.1016/j.neuropharm.2024.110242.
Rafael Rivas-Santisteban 1,  Jaume Lillo 2,  Claudia Garrigós 3,  Gemma Navarro 4,  Rafael Franco 5
Affiliations

Affiliations

  • 1 Laboratory of Computational Medicine, Biostatistics Unit, Faculty of Medicine, Autonomous University of Barcelona, Campus Bellaterra, 08193, Barcelona, Spain; Network Center for Biomedical Research in Neurodegenerative Diseases. CiberNed., Spanish National Health Institute Carlos iii, Av. Monforte de Lemos, 3-5, 28029, Madrid, Spain. Electronic address: rrivasbioq@gmail.com.
  • 2 Network Center for Biomedical Research in Neurodegenerative Diseases. CiberNed., Spanish National Health Institute Carlos iii, Av. Monforte de Lemos, 3-5, 28029, Madrid, Spain; Molecular Neurobiology Laboratory, Dept. Biochemistry and Molecular Biomedicine, Facultat de Biologia, Universitat de Barcelona, 08028, Barcelona, Spain.
  • 3 Molecular Neurobiology Laboratory, Dept. Biochemistry and Molecular Biomedicine, Facultat de Biologia, Universitat de Barcelona, 08028, Barcelona, Spain.
  • 4 Network Center for Biomedical Research in Neurodegenerative Diseases. CiberNed., Spanish National Health Institute Carlos iii, Av. Monforte de Lemos, 3-5, 28029, Madrid, Spain; Department of Biochemistry and Physiology, School of Pharmacy and Food Sciences, Universitat de Barcelona, 08028, Barcelona, Spain.
  • 5 Network Center for Biomedical Research in Neurodegenerative Diseases. CiberNed., Spanish National Health Institute Carlos iii, Av. Monforte de Lemos, 3-5, 28029, Madrid, Spain; Molecular Neurobiology Laboratory, Dept. Biochemistry and Molecular Biomedicine, Facultat de Biologia, Universitat de Barcelona, 08028, Barcelona, Spain; School of Chemistry, Universitat de Barcelona, Barcelona, Spain. Electronic address: rfranco@ub.edu.
PMID: 39613254 DOI: 10.1016/j.neuropharm.2024.110242
Abstract

The physiological role of GPR88, an orphan G protein-coupled receptor (GPCR) predominantly expressed in the striatum, remains unclear, despite its altered expression in parkinsonian animal models. GPR88 is known to interact with Other GPCRs. Specifically, GPR88 expression inhibits signaling mediated by the μ-opioid receptor in cells coexpressing both receptors. The effect of GPR88 on the kappa-opioid receptor (KOR) is less understood. In this study, we examine the interaction between GPR88 and KOR, and the impact of GPR88 expression on KOR-mediated signaling in heterologous cells and primary striatal neurons. Bioluminescence resonance energy transfer and proximity ligation assays revealed an interaction between GPR88 and KOR. Functional assays showed that GPR88 antagonized the effects of U69,593, a selective KOR agonist, on forskolin-stimulated cAMP levels, β-arrestin-2 recruitment, and phosphorylation of extracellular signal-regulated kinases (ERK1/2) in HEK-293T cells coexpressing both receptors. In primary striatal neurons, GPR88 and KOR complexes were observed, with KOR activation effects enhanced when GPR88 expression was suppressed using RNA interference. These results suggest that GPR88 and KOR are coexpressed in striatal neurons, where GPR88 inhibits KOR activation. Notably, the GPR88-KOR heteromer was more prevalent in dopamine D1-receptor-containing neurons of the direct pathway of the basal ganglia. Given the roles of KORs in dopamine release, motor function regulation, and pain and reward perception, the GPR88-KOR interaction warrants further investigation in the context of neuropathic pain, Parkinson's disease, and neuropsychiatric disorders.

Keywords

Basal ganglia; Direct pathway; Kappa opioid receptor; Mitogen-activated protein kinase MAPK; Pain; Parkinson's disease; Reward circuit; Striatonigral neurons; Striatopallidal neurons; cAMP.

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