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Vol. 62, Issue 6, 1385-1392, December 2002
Department of Biochemistry and Molecular Biology I, School of
Biology, Complutense University, Madrid, Spain
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
8-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, 
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.
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