Alpha-adrenergic stimulation of ERK phosphorylation in astrocytes is alpha(2)-specific and may be mediated by transactivation.
The highly specific alpha(2)-adrenergic agonist, dexmedetomidine, has hypnotic-sedative, anesthetic-sparing and analgesic effects, and it protects neurons against ischemia. The alpha(1)-adrenergic agonist, phenylephrine, does not share dexmedetomidine's pharmacological properties, although both dexmedetomidine and phenylephrine increase free cytosolic Ca(2+) ([Ca(2+)](i)) in astrocytes, and most of dexmedetomidine's actions in the brain are exerted on postjunctional receptors. alpha(2)-Adrenergic receptors are abundant on astrocytes. Dexmedetomidine-mediated 'down-streamn' signal transduction was therefore investigated in primary cultures of mouse astrocytes and contrasted with that of phenylephrine. The cultures were incubated with dexmedetomidine concentrations known to be pharmacologically active and to act specifically on alpha(2)-adrenergic receptors (25-100 nM). ERK(1/2) phosphorylation was measured using specific antibodies. Peak increases of ERK(1/2) phosphorylation occurred at 50 nM dexmedetomidine, with less effect at higher concentrations. Phenylephrine caused ERK phosphorylation only at a concentration high enough to exert non subtype-specific effects (10 microM), and this effect was counteracted by the alpha(2)-adrenergic antagonist atipamezole. The phosphorylation of ERK was reduced by tyrphostin AG1478, an inhibitor of phosphorylation of the epidermal growth factor receptor (EGFR), and by heparin, which neutralizes heparin-binding epithelial growth factor (HB-EGF), suggesting the involvement of a transactivation process, in which alpha(2)-adrenergic stimulation leads to proteolytic shedding of HB-EGF (and perhaps other EGFR agonists) from transmembrane-spanning precursors.
Peng
Liang
L
Hong Kong DNA Chips Limited, Hong Kong, Kowloon, China.
Yu
Albert C H
AC
Fung
King Y
KY
Prévot
Vincent
V
Hertz
Leif
L
D058647:Adrenergic alpha-2 Receptor Agonists; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005343:Fibrinolytic Agents / Q000494:pharmacology; D006493:Heparin / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000145:classification / Q000378:metabolism*; D010656:Phenylephrine / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011799:Quinazolines; D013997:Time Factors; D015533:Transcriptional Activation; D020032:Tyrphostins / Q000494:pharmacology
D058647:Adrenergic alpha-2 Receptor Agonists; D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D004791:Enzyme Inhibitors; D005343:Fibrinolytic Agents; D007093:Imidazoles; D011799:Quinazolines; D020032:Tyrphostins; C050701:atipamezole; C101044:RTKI cpd; D010656:Phenylephrine; D006493:Heparin; D020928:Mitogen-Activated Protein Kinases