Journal
BRITISH JOURNAL OF PHARMACOLOGY
Volume 154, Issue 1, Pages 191-203Publisher
WILEY
DOI: 10.1038/bjp.2008.58
Keywords
ERK; PKC; gene expression; beta gamma subunits of G(i) protein; Src kinase; metalloproteinase; neuroprotection; paracrine effect of EGF receptor ligand
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Background and purpose: Stimulation of astrocytes by the alpha(2)-adrenoceptor agonist dexmedetomidine, a neuroprotective drug, transactivates epidermal growth factor (EGF) receptors. The present study investigates signal pathways leading to release of an EGF receptor ligand and those activated during EGF receptor stimulation, and the response of neurons to dexmedetomidine and to astrocyte-conditioned medium. Experimental approach: Phosphorylation of ERK1/2 was determined by western blotting and immunocytochemistry, and phosphorylation of EGF receptors by immunoprecipitation and western blotting. mRNA expression of fos family was measured by RT-PCR. Key results: Pertussis toxin (0.2 mu g ml(-1)) an inhibitor of G alpha(i) subunit dissociation from G alpha(i) protein, and GF 109203X (500 nM), a protein kinase C inhibitor, abolished ERK1/2 phosphorylation. PP1 (10 mu M), inhibiting Src kinase and GM 6001 (10 mu M), an inhibitor of Zn-dependent metalloproteinase, abolished ERK1/2 phosphorylation by dexmedetomidine (50 nM), but not that by EGF (10 ng ml(-1)), showing Src kinase and metalloproteinase activation during the first stage only; AG 1478 (1 mM), an inhibitor of the EGF receptor tyrosine kinase, abolished ERK1/2 phosphorylation. Dexmedetomidine-induced EGF receptor phosphorylation was prevented by AG 1478, GM 6001, PP1 and GF 109203X and its induction of cfos and fosB by AG 1478 and by U0126 (10 mM), an inhibitor of ERK phosphorylation, indicating downstream effects of ERK1/2 phosphorylation. EGF and conditioned medium from dexmedetomidine-treated astrocytes, but not dexmedetomidine itself, induced ERK phosphorylation in primary cultures of cerebellar neurons. Conclusions and implications: Dexmedetomidine-induced transactivation pathways were delineated. Its paracrine effect on neurons may account for its neuroprotective effects.
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