Activation of mitogen-activated protein kinases by stimulation of the central cannabinoid receptor CB1

Abstract

The G-protein-coupled central cannabinoid receptor (CB1) has been shown to be functionally associated with several biological responses including inhibition of adenylate cyclase, modulation of ion channels and induction of the immediate-early gene Krox-24. Using stably transfected Chinese Hamster Ovary cells expressing human CB1 we show here that cannabinoid treatment induces both phosphorylation and activation of mitogen-activated protein (MAP) kinases, and that these effects are inhibited by SR 141716A, a selective CB1 antagonist. The two p42 and p44 kDa MAP kinases are activated in a time- and dose-dependent manner. The rank order of potency for the activation of MAP kinases with various cannabinoid agonists is CP-55940 > delta 9-tetrahydrocannabinol > WIN 55212.2, in agreement with the pharmacological profile of CB1. The activation of MAP kinases is blocked by pertussis toxin but not by treatment with hydrolysis-resistant cyclic AMP analogues. This suggests that the signal transduction pathway between CB1 and MAP kinases involves a pertussis-toxin-sensitive GTP-binding protein and is independent of cyclic AMP metabolism. This coupling of CB1 subtype and mitogenic signal pathway, also observed in the human astrocytoma cell line U373 MG, may explain the mechanism of action underlying cannabinoid-induced Krox-24 induction.

Activation of mitogen-activated protein kinase couples neurotensin receptor stimulation to induction of the primary response gene Krox-24

“…First, the increase in Krox-24 gene expression can be used as a marker for studying the molecular events associated with NTR stimulation. Secondly, we recently published results demonstrating the involvement of the GPC cannabinoid receptors in Krox-24 activation mediated by MAPK [52]. The results reported here provide an additional example of a GPCR that can activate Krox-24.…”

L-type channel inhibition by CB1 cannabinoid receptors is mediated by PTX-sensitive G proteins and cAMP/PKA in GT1-7 hypothalamic neurons

“…Their effects are most commonly mediated by the CB1 cannabinoid receptor (CB1R), which is highly expressed in a variety of brain regions, including the hypothalamus [3][4][5]. The CB1R is a member of the G protein-coupled receptor superfamily [6] which acts by inhibiting adenylate cyclase (AC) activity [7], delaying the opening of voltage-gated N-and P/Q-type channels [8][9][10][11], activating K + channels [12,13] and triggering MAP kinases signal cascades [14]. All these effects are originated from the activation of PTX-sensitive G i,o proteins coupled to CB1Rs, which inhibit AC activity and reduces cytoplasmic cAMP levels.…”

Δ9-Tetrahydrocannabinol-Induced Apoptosis in Jurkat Leukemia T Cells Is Regulated by Translocation of Bad to Mitochondria

“…In normal and transfected neural cells, vascular endothelial cells, and Chinese hamster ovary cells, cannabinoid treatment was shown to induce activation of ERK (12), c-Jun NH 2 -terminal kinase (JNK), and p38 (13,14). In contrast, it was shown that cannabinoids were cytotoxic in leukemic cells and that they inhibited neuronal progenitor cell differentiation through attenuation of the ERK pathway (15).…”