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Pathways and roadblocks in muscarinic receptor-mediated growth regulation

J H Brown1, V Sah, S Moskowitz

  • 1Department of Pharmacology, University of California San Diego, La Jolla 92093, USA.

Life Sciences
|January 1, 1997
PubMed

Insights

Muscarinic receptor stimulation can trigger cell growth, but effectiveness varies by subtype and cell type. Specific G-proteins like G12 are crucial for mediating these growth responses in certain cell systems.

Area of Science:

  • Cell biology
  • Molecular pharmacology
  • Signal transduction

Background:

  • Muscarinic receptor stimulation can induce cell proliferation and transformation in a subtype- and cell-type-specific manner.
  • While m1 and m3 muscarinic receptors can stimulate phospholipase C, they do not always induce DNA synthesis or mitogenesis.
  • The thrombin receptor, also coupling to phospholipase C, is mitogenic and induces AP-1-dependent gene expression in 1321N1 astrocytoma cells.

Purpose of the Study:

  • To investigate the reasons behind the differential mitogenic effects of muscarinic receptors compared to other G-protein-coupled receptors.
  • To explore the role of specific G-proteins, particularly G12 and Rho subfamily proteins, in mediating receptor-induced cell growth.
  • To understand the signaling pathways involved in muscarinic receptor-induced hypertrophy in cardiomyocytes.

Main Methods:

  • Utilizing 1321N1 astrocytoma cells and cardiomyocytes as model systems.
  • Investigating receptor coupling to G-proteins, including pertussis toxin-sensitive and insensitive pathways.
  • Employing chimeric receptors to dissect signaling requirements for hypertrophy.
  • Analyzing DNA synthesis, gene expression (AP-1), and morphological changes.

Main Results:

  • Activation of m3 receptors in 1321N1 cells stimulates phospholipase C but not DNA synthesis, unlike the thrombin receptor.
  • Muscarinic receptor number and selective coupling to G12 may limit mitogenic signaling.
  • Heterologously expressed m1 or m3 receptors induce hypertrophic cell growth in cardiomyocytes, requiring phospholipase C signaling and additional factors.
  • Small G-proteins of the Rho subfamily, alongside G12, are implicated in mediating growth responses.

Conclusions:

  • The mitogenic potential of muscarinic receptor stimulation is dependent on cell type and specific downstream signaling pathways, including G-protein coupling.
  • G-protein coupling efficiency and the involvement of specific G-proteins like G12 and Rho are critical determinants of cell growth responses.
  • While phospholipase C activation is necessary for hypertrophy, additional signals are required for the full morphological manifestation of this growth response.

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