Τόμος 25 (2007) – Τεύχος 1 – Άρθρο 3 – Επιθεώρηση Κλινικής Φαρμακολογίας και Φαρμακοκινητικής-Ελληνική Έκδοση – Volume 25 (2007) – Issue 1– Article 3 – Epitheorese Klinikes Farmakologias και Farmakokinetikes-Greek Edition

Διενεργοποίηση του Υποδοχέα του Επιδερμικού Αυξητικού Παράγοντα EGFR από Αγωνιστές του Κανναβινοειδούς Υποδοχέα CB₁

Transactivation of Epidermal Growth Factor Receptor EGFR by CB₁ Cannabinoid Receptor Agonists

Ελληνικά – Greek

Άρθρο

Article

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Cannabinoids have long been used as therapeutic agents. The recent identification of the endogenous cannabinoid system in the brain, namely the abun­dance of the CB₁ receptor (CB₁R) in the CNS and the discovery of the endogenous ligands, has sug­gested that the cannabinoid neuro­modulatory sys­tem plays important roles in many physiological processes, such as in memory, as well as holds therapeutic promise in a wide range of diseases ranging from mood and anxiety disorders to move­ment disorders and spinal cord injury. The CB₁ receptor exerts its effects through several signal­ling events, which include the activation of the ex­tracellular signal-regulated kinase, or ERKs. The mechanism by which this G-protein coupled recep­tor triggers ERK activation is not, however, well understood. To investigate the molecular events coupling CB1 activation to PKC and ERK activation, we generated clonal SHSY-5Y neuroblastoma cell lines which stably overexpress EGFP-CB₁R and assessed whether this coupling could be mediated via transactivation of growth factor receptors with intrinsic tyrosine kinase activity. We first established using both immunoprecipitation and immunocyto­chemistry and GFP fluorescent imaging that the EGFP-CB₁R was properly glycosylated and tar­geted to plasma membranes. We now report that the CB₁R agonist methanandamide specifically stimulated, in a time-dependent manner, tyrosine phosphorylation of several cellular proteins, includ­ing phosphorylation of the EGF receptor and Src kinase on tyrosine residues 1148 and 416, respec­tively, and of ERK₂. These effects were abolished by the specific CB₁ antagonist AM251 and by the EGFR antagonist AG1478. These data provide first evidence that in a neuronal cellular back­ground, the CB₁R intracellular signalling engages the specific transactivation of the tyrosine kinase EGF receptor to regulate ERK activation and downstream transcrip­tional events