Signaling Pathway Associated with Stimulation of CB2 Peripheral Cannabinoid Receptor

Abstract

Cannabinoids, known for their psychoactive effects, also possess iminunomodulatory properties. The recent isolation and cloning of the G-protein-coupled peripheral cannabinoid receptor (CB2), mainly expressed in immune tissues, have provided molecular tools to determine how cannabinoid compounds may mediate immunomodulation. We here investigated the CB2 signaling properties using stably transfected Chinese hamster ovary cells expressing human CB2. First, we showed that stimulation by a cannabinoid agonist activated mitogen-activated protein (MAP) kinase in time-and dose-dependent manners. The rank order of potency for MAP kinase activation of cannabinoid agonists correlated well with their binding capacities. Second, we demonstrated that, following MAP kinase activation, cannabinoids induced the expression of the growth-related gene Krox-24, also known as NGFI-A, 28268, and egr-1 .Pertussis toxin completely prevented both MAP kinase activation and Krox-24 induction, even more these responses appeared to be dependent of specific proteine kinase C isoforms and independent of inhibition of adenylyl cyclase. A similar coupling of CB2 to a mitogenic pathway and to the regulation of Krox-24 expression was also observed in human promyelocytic cells HL60. Taken together, these findings provide evidence for a functional role of the CB2 receptor in gene induction mediated by the MAP kinase network.Keywords: peripheral cannabinoid receptor; cannabinoid receptor CB2 ; mitogen-activated protein kinase ; Krox-24: cannabinoid.A'-Tetrahydrocannabinol, the major active component of marijuana as well as other cannabinoids, is known to exert a wide range of physiological effects : drowsiness, alterations in cognition and memory, analgesia, as well as anti-inflammatory and immunomodulatory effects [I, 21. Many studies have been conducted to decipher the complexity of the cannabinoid system. First attributed to nonspecific cell membrane alterations, the cannabinoid effects are now known to be mediated through cannabinoid receptors. Two proteins with seven transmembranespanning domains typical of G-protein-coupled receptors have been identified as tetrahydrocannabinol receptors and referred to as CBI and CB2.The CBI receptor is predominantly expressed in the brain [3, 41 and could account for the psychoactive effects of cannabinoids. This receptor is also found in the periphery but at a much lower abundance [5-71. Several signaling pathways triggered by the stimulation of CBI have already been described, all being sensitive to pertussis toxin (PTX). Activation of CBI inhibits adenylyl cyclase activity [8J as well as voltage-depenCorrespondence to P. Casellas, Sanofi Recherche, 371 rue du Pr. Joseph Blayac, F-34184 Montpellier cedex 04, France.Abbrevintions. MAP, mitogen-activated protein; MBP, myelin basic protein; CHO, Chinese hamster ovary; CB1, central cannabinoid receptor; CB2, peripheral cannabinoid receptor; Br*cAMP, 8-bromoadenosine 3',S'-monophosphate; Bt,cAMP, P,2'-dibutyryl-adenosine 3',S'-monophosphate; EMSA, electrophoret...

The extracellular regulated kinases (ERK) 1/2 mediate cannabinoid‐induced inhibition of gap junctional communication in endothelial cells

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Activation through Cannabinoid Receptors 1 and 2 on Dendritic Cells Triggers NF-κB-Dependent Apoptosis: Novel Role for Endogenous and Exogenous Cannabinoids in Immunoregulation

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