Cannabinoid CB2 receptor ligands disrupt the sequential regulation of p-MEK1/2 to p-ERK1/2 in mouse brain cortex
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Published:2023-10-24
Issue:5
Volume:3
Page:258-267
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ISSN:
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Container-title:Exploration of Neuroprotective Therapy
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language:en
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Short-container-title:Explor Neuroprot Ther
Author:
Salort Glòria1ORCID, Álvaro-Bartolomé María2ORCID, García-Sevilla Jesús A.2ORCID
Affiliation:
1. Laboratory of Neuropharmacology, IUNICS, UIB, E-07122 Palma de Mallorca, Spain; Pharmacology Unit, Department of Pathology and Experimental Therapeutics, Faculty of Medicine and Health Sciences, Institute of Neurosciences, University of Barcelona, 08907 L’Hospitalet de Llobregat, Spain; Neuropharmacology and Pain Group, Neuroscience Program, Institut d’Investigació Biomèdica de Bellvitge, IDIBELL, 08907 L’Hospitalet de Llobregat, Spain 2. Laboratory of Neuropharmacology, Institut Universitari d’Investigació en Ciències de la Salut (IUNICS), University of the Balearic Islands (UIB), E-07122 Palma de Mallorca, Spain
Abstract
Aim: The sequential phosphorylation of mitogen-activated protein (MAP) kinases MEK-ERK is the most relevant cellular signaling pathway. This study quantified the parallel in vivo regulation of brain phosphorylation-MEK1/2 (p-MEK1/2) to p-ERK1/2 by mechanistically different cannabinoid 2 (CB2) receptor ligands, i.e., direct (and endogenous) agonists and inverse agonists.
Methods: Groups of Swiss albino CD1 IGS male adult mice were treated (i.p.) with the CB2 agonist JWH133 (1 mg/kg and 3 mg/kg, 1 h, n = 8) or the CB2 inverse agonist/antagonist AM630 (0.3 mg/kg and 1 mg/kg, 1.5 h, n = 8–9), and 0.9% NaCl (2 mL/kg, 1 h, n = 4–10) as vehicle control. Transgenic male mice overexpressing cortical CB2 receptors [messenger RNA (mRNA) and protein] on a Swiss ICR congenic background (CB2xP) and the corresponding littermates age-matched wild-type (WT) controls were used. Protein forms (total MEK and ERK p-kinases) were resolved by electrophoresis [sodium dodecyl-sulfate polyacrylamide gel electrophoresis (SDS-PAGE) minigels] followed by immunoblotting standard procedures.
Results: The selective CB2 agonist JWH133 (1 mg/kg and 3 mg/kg, i.p., 1 h) modestly decreased MEK (17%, n = 8) and upregulated ERK (25%, n = 8) activities. The endogenous CB2 agonists (acting on promoted overexpressed receptors) decreased MEK (44%, n = 9) and upregulated ERK (67%, n = 10) activities. The inverse agonist/antagonist AM630 (0.3 mg/kg and 1 mg/kg, i.p., 1.5 h) increases MEK activity (27%, n = 8) without significantly altering that of ERK (5%, n = 9).
Conclusions: Acute treatments of mice with mechanistically different CB2 receptor ligands (i.e., direct agonists, endogenous agonists, and inverse agonists) resulted in disruption of MEK (p-MEK/total-MEK ratio) to ERK (p-ERK/total-ERK ratio) signals in the brain cortex. This striking disruption of MEK to ERK parallel regulation in the cannabinoid CB2 receptor system in the brain could be relevant to the postulated role of CB2 receptors in various central nervous system (CNS) diseases.
Funder
Ministerio de Economía y Competitividad European Regional Development Fund
Publisher
Open Exploration Publishing
Subject
General Medicine,General Medicine,General Energy,General Earth and Planetary Sciences,General Environmental Science,General Earth and Planetary Sciences,General Environmental Science,General Medicine,General Medicine,Genetics,Animal Science and Zoology,General Earth and Planetary Sciences,General Environmental Science,Insect Science,Ecology,Ecology, Evolution, Behavior and Systematics
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