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Norepinephrine activates extracellular-regulated kinase in cortical neurons
Lara M Tolbert1, David S Russell, Ronald S Duman
1Departments of Psychiatry and Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06508, USA.
Biological Psychiatry
|November 20, 2003
Summary
Norepinephrine activates the mitogen-activated protein kinase cascade through alpha(2)- and beta-adrenergic receptors. This signaling pathway is independent of neurotrophic factors, utilizing tyrosine kinases rather than classical second-messenger pathways.
Area of Science:
- Neuroscience
- Cellular Signaling
- Molecular Biology
Background:
- Antidepressants indirectly activate monoamine receptors, increasing neurotrophic factors and mitogen-activated protein kinase (MAPK) cascade.
- Investigates potential direct influence of monoamine receptors on the MAPK pathway, independent of neurotrophic factors.
Purpose of the Study:
- Characterize the influence of norepinephrine on extracellular-regulated protein kinase (ERK) phosphorylation.
- Elucidate the specific signaling pathways involved in norepinephrine-induced ERK activation.
Main Methods:
- Primary cerebral cortical cultures from embryonic day 18 rat brains were utilized.
- Cells were incubated with norepinephrine, with or without agents targeting adrenergic receptors or intracellular signaling proteins.
- Phosphorylated ERK levels were quantified using immunoblotting.
Main Results:
- Norepinephrine induced a time- and dose-dependent increase in phosphorylated ERK.
- Activation of alpha(2)- and beta-adrenergic receptor subtypes was crucial for this effect.
- Norepinephrine-induced ERK activation required a pertussis toxin-sensitive G protein, a receptor tyrosine kinase, and phosphatidylinositol 3-kinase.
Conclusions:
- Norepinephrine activates the MAPK cascade via a tyrosine kinase-dependent pathway.
- This activation is independent of classical second-messenger or Src-dependent kinases.
- Suggests a distinct signaling mechanism for norepinephrine in neuronal cells.