RT Journal Article SR Electronic T1 Mechanism of Extracellular Signal-Regulated Kinase Activation by the CB1 Cannabinoid Receptor JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP 1385 OP 1392 DO 10.1124/mol.62.6.1385 VO 62 IS 6 A1 Ismael Galve-Roperh A1 Daniel Rueda A1 Teresa Gómez del Pulgar A1 Guillermo Velasco A1 Manuel Guzmán YR 2002 UL http://molpharm.aspetjournals.org/content/62/6/1385.abstract AB Cannabinoids, the active components of marijuana and their endogenous counterparts, exert many of their actions in brain through the seven-transmembrane receptor CB1. This receptor is coupled to the activation of the extracellular signal-regulated kinase (ERK) cascade. However, the precise molecular mechanism for CB1-mediated ERK activation is still unknown. Here, we show that in U373 MG human astrocytoma cells, CB1 receptor activation with the cannabinoid agonist Δ8-tetrahydrocannabinol dimethyl heptyl (HU-210) was coupled to ERK activation and protection from ceramide-induced apoptosis. HU-210-induced ERK activation was inhibited by tyrphostin AG1478 and PP2, widely employed inhibitors of the epidermal growth factor receptor (EGFR) and the Src family of cytosolic tyrosine kinases, respectively. However, HU-210 stimulation resulted in neither EGFR phosphorylation, Src tyrosine phosphorylation, nor increased Src activity. In addition, dominant-negative forms of both proteins were unable to prevent cannabinoid-induced ERK activation, thus excluding the existence of CB1-mediated EGFR transactivation or Src activation. Wortmannin and 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294,002), inhibitors of the phosphatidylinositol 3-kinase (PI3K) signaling pathway, blocked cannabinoid-induced ERK activation. Likewise, HU-210 stimulated the PI3K downstream targets protein kinase B (PKB), as shown by its phosphorylation in Thr 308 and Ser 473 residues, and Raf-1. Moreover, βγ subunit release mimicked ERK and PI3K/PKB activation, suggesting that activation of class IB PI3K mediates cannabinoid action. Pro-survival HU-210 action also required activation of both PI3K and ERK signaling pathways. In conclusion, CB1-induced ERK activation was mediated by PI3KIB and this effect may have important consequences in the control of cell death/survival decision.