title: Orchestrated activation of mGluR5 and CB1 promotes neuroprotection.
abstract: The metabotropic glutamate receptor 5 (mGluR5) and the cannabinoid receptor 1 (CB1) exhibit a functional interaction, as CB1 regulates pre-synaptic glutamate release and mGluR5 activation increases endocannabinoid synthesis at the post-synaptic site. Since both mGluR5 and CB1 promote neuroprotection, we delineated experiments to investigate a possible link between CB1 and mGluR5 activation in the induction of neuroprotection using primary cultured corticostriatal neurons. We find that either the pharmacological blockade or the genetic ablation of either mGluR5 or CB1 can abrogate both CB1- and mGluR5-mediated neuroprotection against glutamate insult. Interestingly, decreased glutamate release and diminished intracellular Ca(2+) do not appear to play a role in CB1 and mGluR5-mediated neuroprotection. Rather, these two receptors work cooperatively to trigger the activation of cell signaling pathways to promote neuronal survival, which involves MEK/ERK1/2 and PI3K/AKT activation. Interestingly, although mGluR5 activation protects postsynaptic terminals and CB1 the presynaptic site, intact signaling of both receptors is required to effectively promote neuronal survival. In conclusion, mGluR5 and CB1 act in concert to activate neuroprotective cell signaling pathways and promote neuronal survival.
authors.affiliation: Departamento de Bioquimica e Imunologia, Instituto de Ciencias Biologicas, Universidade Federal de Minas Gerais, Ave. Antonio Carlos 6627, Belo Horizonte, MG, CEP: 31270-901, Brazil.
authors.forename: Edleusa M L
authors.initials: EM
authors.lastname: Batista
authors.affiliation: Departamento de Bioquimica e Imunologia, Instituto de Ciencias Biologicas, Universidade Federal de Minas Gerais, Ave. Antonio Carlos 6627, Belo Horizonte, MG, CEP: 31270-901, Brazil.
authors.forename: Juliana G
authors.initials: JG
authors.lastname: Doria
authors.affiliation: Departamento de Bioquimica e Imunologia, Instituto de Ciencias Biologicas, Universidade Federal de Minas Gerais, Ave. Antonio Carlos 6627, Belo Horizonte, MG, CEP: 31270-901, Brazil.
authors.forename: Talita H
authors.initials: TH
authors.lastname: Ferreira-Vieira
authors.affiliation: Departamento de Bioquimica e Imunologia, Instituto de Ciencias Biologicas, Universidade Federal de Minas Gerais, Ave. Antonio Carlos 6627, Belo Horizonte, MG, CEP: 31270-901, Brazil.
authors.forename: Juliana
authors.initials: J
authors.lastname: Alves-Silva
authors.affiliation: Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, K1H8M5, Canada.
authors.forename: Stephen S G
authors.initials: SS
authors.lastname: Ferguson
authors.affiliation: Departamento de Farmacologia, Instituto de Ciencias Biologicas, Universidade Federal de Minas Gerais, Belo Horizonte, 31270-901, Brazil.
authors.forename: Fabricio A
authors.initials: FA
authors.lastname: Moreira
authors.affiliation: Departamento de Bioquimica e Imunologia, Instituto de Ciencias Biologicas, Universidade Federal de Minas Gerais, Ave. Antonio Carlos 6627, Belo Horizonte, MG, CEP: 31270-901, Brazil. fmribeiro@icb.ufmg.br.
authors.forename: Fabiola M
authors.initials: FM
authors.lastname: Ribeiro
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D052117:Benzodioxoles / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002219:Carbamates / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D055785:Gene Knockdown Techniques; D042541:Intracellular Space / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D000066829:Neuroprotection; D010766:Phosphorylation / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology; D017729:Presynaptic Terminals / Q000187:drug effects / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D064529:Receptor, Metabotropic Glutamate 5 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013569:Synapses / Q000187:drug effects / Q000378:metabolism
chemical_list: C494553:3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide; D001549:Benzamides; D052117:Benzodioxoles; D002219:Carbamates; C534333:JZL 184; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D064529:Receptor, Metabotropic Glutamate 5; C500528:cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D002118:Calcium
keywords: AKT; CB1; Cell death; ERK1/2; mGluR5