Expression of GPR55 and either cannabinoid CB 1 or CB 2 heteroreceptor complexes in the caudate, putamen, and accumbens
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ORIGINAL ARTICLE
Expression of GPR55 and either cannabinoid CB1 or CB2 heteroreceptor complexes in the caudate, putamen, and accumbens nuclei of control, parkinsonian, and dyskinetic non‑human primates Eva Martínez‑Pinilla1,2,3 · Alberto J. Rico4,5,6 · Rafael Rivas‑Santisteban6,7 · Jaume Lillo6,7 · Elvira Roda4,5,6 · Gemma Navarro6,8 · José Luis Lanciego4,5,6 · Rafael Franco6,7 Received: 27 March 2020 / Accepted: 9 July 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Endocannabinoids are neuromodulators acting on specific cannabinoid C B1 and C B2 G-protein-coupled receptors (GPCRs), representing potential therapeutic targets for neurodegenerative diseases. Cannabinoids also regulate the activity of GPR55, a recently “deorphanized” GPCR that directly interacts with CB1 and with CB2 receptors. Our hypothesis is that these heteromers may be taken as potential targets for Parkinson’s disease (PD). This work aims at assessing the expression of heteromers made of GPR55 and CB1/CB2 receptors in the striatum of control and parkinsonian macaques (with and without levodopainduced dyskinesia). For this purpose, double blind in situ proximity ligation assays, enabling the detection of GPCR heteromers in tissue samples, were performed in striatal sections of control, MPTP-treated and MPTP-treated animals rendered dyskinetic by chronic treatment with levodopa. Image analysis and statistical assessment were performed using dedicated software. We have previously demonstrated the formation of heteromers between GPR55 and C B1 receptor ( CB1-GPR55_ Hets), which is highly expressed in the central nervous system (CNS), but also with the CB2 receptor (CB2-GPR55_Hets). Compared to the baseline expression of CB1-GPR55_Hets in control animals, our results showed increased expression levels in basal ganglia input nuclei of MPTP-treated animals. These observed increases in C B1-GPR55_Hets returned back to baseline levels upon chronic treatment with levodopa in dyskinetic animals. Obtained data regarding C B2-GPR55_Hets were quite similar, with somehow equivalent amounts in control and dyskinetic animals, and with increased expression levels in MPTP animals. Taken together, the detected increased expression of GPR55-endocannabinoid heteromers appoints these GPCR complexes as potential non-dopaminergic targets for PD therapy. Keywords G-protein coupled receptor (GPCR) heteromer · Levodopa · Parkinson’s disease · Proximity ligation assay (PLA) · Striatum Eva Martínez-Pinilla, Alberto J. Rico, Gemma Navarro, José Luis Lanciego and Rafael Franco contributed equally to this work. 4
* José Luis Lanciego [email protected]
Neurosciences Division, Centre for Applied Medical Research, CIMA, University of Navarra, Avenida Pío XII, 55, 31008 Pamplona, Spain
5
* Rafael Franco [email protected]; [email protected]
Instituto de Investigaciones Sanitarias de Navarra (IdiSNA), Pamplona, Spain
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Centro de Investigación Biomédica en Red Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
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