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Brain Behav Immun. 2018 Jan;67:139-151. doi: 10.1016/j.bbi.2017.08.015. Epub 2017 Aug 24.

Receptor-heteromer mediated regulation of endocannabinoid signaling in activated microglia. Role of CB1 and CB2 receptors and relevance for Alzheimer's disease and levodopa-induced dyskinesia.

Author information

1
Molecular Neurobiology laboratory, Department of Biochemistry and Molecular Biomedicine, University of Barcelona, Diagonal 643, 08028 Barcelona, Spain; Centro de Investigación en Red, Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, C/ Sinesio Delgado, 4, 28029 Madrid, Spain; Dept. Biochemistry and Physiology, Pharmacy School, Universitat de Barcelona, Diagonal 645, 08028 Barcelona, Spain.
2
Department of Neuroscience, Karolinska Institutet, Retzius väg 8., 17177 Stockholm, Sweden.
3
Molecular Neurobiology laboratory, Department of Biochemistry and Molecular Biomedicine, University of Barcelona, Diagonal 643, 08028 Barcelona, Spain; Centro de Investigación en Red, Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, C/ Sinesio Delgado, 4, 28029 Madrid, Spain.
4
Department of Biomedicine, Biochemistry and Molecular Biology Unit, School of Medicine, University of Barcelona, IDIBAPS, Barcelona, Spain; Institute of Neurosciences, University of Barcelona, Barcelona, Spain.
5
Centro de Investigación en Red, Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, C/ Sinesio Delgado, 4, 28029 Madrid, Spain; Laboratory of Neuroanatomy and Experimental Neurology, Department of Morphological Sciences, Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), University of Santiago de Compostela, Barcelona ave. s/n, 15782 Santiago de Compostela, Spain.
6
Centro de Investigación en Red, Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, C/ Sinesio Delgado, 4, 28029 Madrid, Spain; Neuroscience Department, Center for Applied Medical Research (CIMA), University of Navarra, Avida Pio XII, 55., 31008 Pamplona, Spain.
7
Centro de Investigación en Red, Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, C/ Sinesio Delgado, 4, 28029 Madrid, Spain; Institut de Neurociències, Department de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Campus Bellaterra. Plaça Cívica, s/n, 08193 Bellaterra, Spain.
8
Molecular Neurobiology laboratory, Department of Biochemistry and Molecular Biomedicine, University of Barcelona, Diagonal 643, 08028 Barcelona, Spain; Centro de Investigación en Red, Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, C/ Sinesio Delgado, 4, 28029 Madrid, Spain. Electronic address: rfranco@ub.edu.

Abstract

Endocannabinoids are important regulators of neurotransmission and, acting on activated microglia, they are postulated as neuroprotective agents. Endocannabinoid action is mediated by CB1 and CB2 receptors, which may form heteromeric complexes (CB1-CB2Hets) with unknown function in microglia. We aimed at establishing the expression and signaling properties of cannabinoid receptors in resting and LPS/IFN-γ-activated microglia. In activated microglia mRNA transcripts increased (2 fold for CB1 and circa 20 fold for CB2), whereas receptor levels were similar for CB1 and markedly upregulated for CB2; CB1-CB2Hets were also upregulated. Unlike in resting cells, CB2 receptors became robustly coupled to Gi in activated cells, in which CB1-CB2Hets mediated a potentiation effect. Hence, resting cells were refractory while activated cells were highly responsive to cannabinoids. Interestingly, similar results were obtained in cultures treated with ß-amyloid (Aß1-42). Microglial activation markers were detected in the striatum of a Parkinson's disease (PD) model and, remarkably, in primary microglia cultures from the hippocampus of mutant β-amyloid precursor protein (APPSw,Ind) mice, a transgenic Alzheimer's disease (AD) model. Also of note was the similar cannabinoid receptor signaling found in primary cultures of microglia from APPSw,Ind and in cells from control animals activated using LPS plus IFN-γ. Expression of CB1-CB2Hets was increased in the striatum from rats rendered dyskinetic by chronic levodopa treatment. In summary, our results showed sensitivity of activated microglial cells to cannabinoids, increased CB1-CB2Het expression in activated microglia and in microglia from the hippocampus of an AD model, and a correlation between levodopa-induced dyskinesia and striatal microglial activation in a PD model. Cannabinoid receptors and the CB1-CB2 heteroreceptor complex in activated microglia have potential as targets in the treatment of neurodegenerative diseases.

KEYWORDS:

Endocannabinoid; G-protein-coupled receptor; GPCR; GPCR heteromer; Heterodimers; Heteromers

PMID:
28843453
DOI:
10.1016/j.bbi.2017.08.015
[Indexed for MEDLINE]

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