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Signalling pathways for transactivation by dexmedetomidine of epidermal growth factor receptors in astrocytes and its paracrine effect on neurons
Author(s) -
Li B,
Du T,
Li H,
Gu L,
Zhang H,
Huang J,
Hertz L,
Peng L
Publication year - 2008
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/bjp.2008.58
Subject(s) - mapk/erk pathway , phosphorylation , mek inhibitor , epidermal growth factor , biology , transactivation , proto oncogene tyrosine protein kinase src , microbiology and biotechnology , chemistry , endocrinology , medicine , receptor , biochemistry , gene expression , gene
Background and purpose: Stimulation of astrocytes by the α 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 ERK 1/2 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 μg ml −1 ) an inhibitor of βγ subunit dissociation from Gα i protein, and GF 109203X (500 n M ), a protein kinase C inhibitor, abolished ERK 1/2 phosphorylation. PP1 (10 μ M ), inhibiting Src kinase and GM 6001 (10 μ M ), an inhibitor of Zn‐dependent metalloproteinase, abolished ERK 1/2 phosphorylation by dexmedetomidine (50 n M ), but not that by EGF (10 ng ml −1 ), showing Src kinase and metalloproteinase activation during the first stage only; AG 1478 (1 μ M ), an inhibitor of the EGF receptor tyrosine kinase, abolished ERK 1/2 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 μ M ), an inhibitor of ERK phosphorylation, indicating downstream effects of ERK 1/2 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.