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D(4) dopamine receptor differentially regulates Akt/nuclear factor-kappa b and extracellular signal-regulated kinase

X Zhen1, J Zhang, G P Johnson

  • 1Laboratory of Molecular Pharmacology, Department of Pharmacology and Physiology, MCP Hahnemann School of Medicine, Philadelphia, Pennsylvania, USA.

Molecular Pharmacology
|September 20, 2001
PubMed

Insights

Dopamine D4 receptors activate Akt and ERK pathways through distinct mechanisms. D4 receptor stimulation also drives cell proliferation via the Src/SHC/Ras/ERK pathway, highlighting key signaling roles.

Area of Science:

  • Neuropharmacology
  • Molecular Biology
  • Cell Signaling

Background:

  • Dopamine receptors, particularly the D4 subtype, are implicated in various neurological functions.
  • Understanding the downstream signaling pathways regulated by D4 dopamine receptors is crucial for elucidating their physiological roles.
  • The Akt and extracellular signal-regulated kinase (ERK) pathways are critical for cell survival, proliferation, and differentiation.

Purpose of the Study:

  • To investigate the role of D4 dopamine receptors in regulating the Akt/nuclear factor-kappa B (NF-kappa B) and ERK signaling pathways.
  • To delineate the specific molecular mechanisms underlying D4 receptor-mediated activation of these signaling cascades.
  • To determine the involvement of D4 receptor signaling in cell proliferation.

Main Methods:

  • Utilized D4MN9D cells stably expressing D4 dopamine receptors.
  • Administered D4 dopamine receptor agonist PD168077 and antagonist L745,870.
  • Employed pertussis toxin (PTX) treatment, transfection with kinase-deficient Akt and dominant-negative Ras (N17Ras), and inhibitors like PP2 and PD98059.
  • Assessed activation of Akt, ERK, NF-kappa B, and SHC phosphorylation.

Main Results:

  • D4 dopamine receptor agonist PD168077 dose- and time-dependently activated Akt and ERK pathways.
  • Activation of Akt and ERK was mediated by D4 receptors and required a pertussis toxin-sensitive G protein.
  • NF-kappa B activation was dependent on Akt but independent of Ras, while ERK activation was Ras-dependent.
  • Src kinase activity was essential for D4 receptor-mediated SHC phosphorylation and ERK activation.
  • Distinct signaling mechanisms mediate Akt/NF-kappa B and ERK activation by D4 receptors.
  • D4 receptor-stimulated cell proliferation is driven by the Src/SHC/Ras/ERK pathway.

Conclusions:

  • D4 dopamine receptor stimulation differentially regulates Akt/NF-kappa B and ERK signaling pathways through distinct mechanisms.
  • The Src/SHC/Ras/ERK pathway is critical for D4 receptor-mediated cell proliferation.
  • These findings provide novel insights into the complex signaling networks governed by D4 dopamine receptors.

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