Norepinephrine activates extracellular-regulated kinase in cortical neurons.
BACKGROUND
Previous studies demonstrate that indirect activation of monoamine receptors by antidepressant treatment increases neurotrophic factors that activate the mitogen-activated protein kinase cascade; however, it is also possible that these monoamine receptors influence the mitogen-activated protein kinase pathway independent of neurotrophic factors. The influence of norepinephrine on the phosphorylation of extracellular-regulated protein kinase is characterized.


METHODS
Primary cerebral cortical cultures were prepared from embryonic day 18 rat brains and were subsequently incubated with norepinephrine in the absence or presence of agents acting as noradrenergic receptors or as intracellular signaling proteins. Levels of phosphorylated extracellular-regulated protein kinase were determined by immunoblot.


RESULTS
The results demonstrate that incubation with norepinephrine produces a time- and dose-dependent activation of phosphorylated extracellular-regulated protein kinase and that this increase is dependent on activation of alpha(2)- and beta-adrenergic receptor subtypes. In addition, the results demonstrate that norepinephrine activation of phosphorylated extracellular-regulated protein kinase is dependent on a pertussis toxin-sensitive G protein, a receptor tyrosine kinase, and activation of phosphatidylinositol 3-kinase.


CONCLUSIONS
The findings suggest that activation of the mitogen-activated protein kinase cascade by norepinephrine can occur via a tyrosine kinase-dependent signaling pathway but independent of classical second-messenger or Src-dependent kinases.
Tolbert
Lara M
LM
Departments of Psychiatry and Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06508, USA.
Russell
David S
DS
Duman
Ronald S
RS
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D000068438:Brimonidine Tartrate; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology* / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005110:Extracellular Space / Q000378:metabolism*; D005260:Female; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D009638:Norepinephrine / Q000494:pharmacology*; D037342:Pertussis Toxin / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011224:Prazosin / Q000494:pharmacology; D011247:Pregnancy; D011433:Propranolol / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D015016:Yohimbine / Q000494:pharmacology
D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D004791:Enzyme Inhibitors; D011810:Quinoxalines; D015016:Yohimbine; D000068438:Brimonidine Tartrate; D011433:Propranolol; D037342:Pertussis Toxin; D020928:Mitogen-Activated Protein Kinases; D007545:Isoproterenol; D009638:Norepinephrine; D011224:Prazosin