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G-protein-coupled receptor-mediated activation of rap GTPases: characterization of a novel Galphai regulated pathway

Jacques T Weissman1, Jian-Nong Ma, Anthony Essex

  • 1ACADIA Pharmaceuticals Inc., 3911 Sorrento Valley Blvd, San Diego, CA 92121, USA.

Oncogene
|January 9, 2004
PubMed

Insights

G-protein-coupled receptors (GPCRs) activate Rap proteins, which mediate cellular proliferation. This study reveals a novel pathway involving G-protein alpha subunits, C3G, and Src, elucidating Rap protein signaling in GPCRs.

Area of Science:

  • Cellular signaling
  • Molecular biology
  • G-protein-coupled receptor research

Background:

  • Ras proteins mediate G-protein-coupled receptor (GPCR) proliferative effects.
  • The role of Rap proteins in GPCR signaling remains largely undefined.

Purpose of the Study:

  • To investigate the signaling pathways through which GPCRs activate Rap proteins.
  • To characterize the role of Rap proteins in GPCR-mediated cellular proliferation.

Main Methods:

  • Development of a novel cellular proliferation assay using Ras-Rap chimeras.
  • Utilized activation-specific probes to measure Rap protein activation.
  • Employed pertussis toxin, beta-gamma scavengers, and dominant-negative mutants (C3G, Src) to dissect signaling pathways.

Main Results:

  • Both Gs-coupled (D1 dopamine) and Gi-coupled (5HT1E serotonin) receptors mediated proliferation via Ras/Rap chimeras.
  • Rap proteins were activated by both receptor types, independent of PKA.
  • Gi-coupled receptor signaling to Rap involved Galpha subunits, C3G, and Src, and was pertussis toxin-sensitive.

Conclusions:

  • GPCRs can activate Rap proteins, contributing to cellular proliferation.
  • A novel signaling cascade initiated by Gi-coupled GPCRs involves Galpha subunits, C3G, and Src to activate Rap.
  • Rap proteins represent a significant downstream effector in specific GPCR signaling pathways.

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