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Quantifying Agonist Activity at G Protein-coupled Receptors
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Quantifying Agonist Activity at G Protein-coupled Receptors

Published on: December 26, 2011

Alterations in receptor expression or agonist concentration change the pathways gastrin-releasing peptide receptor

Pei-Wen Chen1, Glenn S Kroog

  • 1Department of Molecular Pharmacology, Albert Eistein College of Medicine, Bronx, New York 10461, USA.

Molecular Pharmacology
|September 14, 2004
PubMed

Insights

Gastrin-releasing peptide receptor (GRPr) activates extracellular signal-regulated kinases (ERKs) through multiple, distinct pathways. These pathways depend on GRPr expression levels and bombesin (BN) concentration, influencing ERK activation and inhibition.

Area of Science:

  • Cellular signaling
  • Molecular biology
  • Receptor pharmacology

Background:

  • G protein-coupled receptors (GPCRs) mediate diverse cellular responses.
  • Extracellular signal-regulated kinases (ERKs) are crucial signaling molecules involved in cell growth and differentiation.
  • The gastrin-releasing peptide receptor (GRPr) is a GPCR implicated in various physiological and pathological processes.

Purpose of the Study:

  • To investigate the distinct signaling pathways employed by GRPr to regulate ERK activation.
  • To determine how GRPr expression levels and agonist concentration influence ERK signaling dynamics.
  • To elucidate the mechanisms underlying GRPr-mediated ERK activation and inhibition.

Main Methods:

  • Utilized stably transfected BALB/c 3T3 fibroblasts with varying GRPr expression levels.
  • Administered different concentrations of bombesin (BN), a GRPr agonist.
  • Analyzed ERK activation and inhibition kinetics, including dependence on GRPr carboxyl-terminal domain (CTD) and sensitivity to protein kinase C inhibition.

Main Results:

  • GRPr induced two distinct waves of ERK activation and one wave of ERK inhibition.
  • The first ERK activation wave was CTD-independent, rapid, and sensitive to inhibitors, occurring at lower BN concentrations/GRPr expression.
  • The second ERK activation wave was CTD-dependent, slower, and observed at higher BN concentrations/GRPr expression.
  • A third pathway led to ERK inhibition at high BN concentrations in cells with high GRPr expression.
  • Endogenous GRPr in a human duodenal cancer cell line also exhibited differential pathway activation.

Conclusions:

  • GRPr employs multiple, distinct signaling pathways to regulate ERK activity within a single cell type.
  • The specific pathway utilized is dependent on GRPr expression levels and agonist concentration.
  • These findings reveal a complex regulatory mechanism of ERK signaling by GRPr with implications for understanding cellular responses and potential therapeutic targets.

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