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The dopamine D4 receptor activates intracellular platelet-derived growth factor receptor beta to stimulate ERK1/2

Robin S Gill1, Marilyn S Hsiung, Chi S Sum

  • 1Centre for Addiction and Mental Health, Toronto, Ontario, Canada.

Cellular Signalling
|September 29, 2009
PubMed

Insights

Dopamine receptors (DRD4) activate intracellular PDGF-beta receptors independently of external growth factors. This signaling pathway bypasses normal receptor maturation, offering new insights into dopamine receptor function.

Area of Science:

  • Neuroscience
  • Cellular Signaling
  • GPCR Research

Background:

  • Dopamine receptors (GPCRs) are crucial for locomotion, reward, and cognition.
  • Previous work showed dopamine receptor transactivation of PDGF-beta receptor (PDGFRbeta) influences ERK1/2 and NMDA receptor activity.

Purpose of the Study:

  • To investigate the mechanism by which dopamine receptor D4 (DRD4) signals to PDGFRbeta.
  • To determine if DRD4 activation of PDGFRbeta is dependent on external growth factors and receptor glycosylation.

Main Methods:

  • Cells were treated with PDGF-BB to induce PDGFRbeta downregulation.
  • Tunicamycin was used to inhibit N-linked glycosylation and maturation of PDGFRbeta.
  • ERK1/2 activation was measured in response to DRD4 signaling and PDGFRbeta kinase inhibition (tyrphostin A9).

Main Results:

  • PDGF-BB-mediated ERK1/2 activation was abolished by PDGFRbeta downregulation.
  • DRD4-mediated ERK1/2 activation was only partially reduced by PDGFRbeta downregulation and remained sensitive to tyrphostin A9.
  • Tunicamycin treatment blocked PDGFRbeta activation by PDGF-BB, but DRD4 signaling to ERK1/2 persisted in a tyrphostin A9-sensitive manner.

Conclusions:

  • Dopamine receptor D4 can activate intracellular PDGFRbeta, independent of external PDGF-BB.
  • This DRD4-mediated signaling bypasses the need for PDGFRbeta maturation and glycosylation.
  • DRD4 utilizes a distinct mechanism to activate PDGFRbeta compared to its cognate ligand, PDGF-BB.

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