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G protein-coupled receptor-mediated mitogen-activated protein kinase activation through cooperation of Galpha(q) and

A Blaukat1, A Barac, M J Cross

  • 1Ludwig Institute for Cancer Research, Uppsala, Sweden.

Molecular and Cellular Biology
|August 25, 2000
PubMed

Insights

Dual-acting G protein-coupled receptors (GPCRs) require cooperation between Gα(i) and Gα(q/11) pathways for robust ERK cascade stimulation. This cooperative signaling is key for regulating cellular responses.

Area of Science:

  • Cellular signaling pathways
  • Molecular biology
  • Pharmacology

Background:

  • G protein-coupled receptors (GPCRs) mediate cellular responses.
  • GPCRs activate extracellular signal-regulated kinases (ERKs) via Gα(q/11) or Gα(i) proteins.
  • Receptors can activate multiple G protein subfamilies simultaneously.

Purpose of the Study:

  • Investigate ERK cascade signaling by receptors activating both Gα(q/11) and Gα(i) proteins.
  • Determine the roles of specific G protein subunits and downstream effectors in ERK activation.
  • Establish the mechanism of signaling for dually coupled GPCRs.

Main Methods:

  • Utilized HEK293T cells and primary fibroblasts (human and mouse).
  • Employed bradykinin B(2) receptor (B(2)R), m(1), and m(3) muscarinic receptors.
  • Assessed ERK2 and Elk1 transcriptional activity, employing Gα(q/11)-deficient cells and constitutively active G protein mutants.

Main Results:

  • B(2)R-induced ERK stimulation depends on Gα(q)-PKC and Gα(i)-Ras pathways.
  • Signaling is independent of Gβγ subunits, PI3K, and tyrosine kinases.
  • Dually coupled GPCRs show synergistic ERK activation requiring both Gα(i) and Gα(q/11) pathways.

Conclusions:

  • Dually coupled GPCRs necessitate cooperative Gα(i) and Gα(q/11) signaling for efficient ERK stimulation.
  • Cooperative signaling by multiple G proteins represents a novel regulatory mechanism for GPCRs.
  • This finding advances understanding of GPCR signaling complexity and cellular regulation.

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