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erbB2 is required for G protein-coupled receptor signaling in the heart

Alejandra Negro1, Bhawanjit K Brar, Yusu Gu

  • 1The Salk Institute, La Jolla, CA 92037, USA.

Proceedings of the National Academy of Sciences of the United States of America
|October 18, 2006
PubMed

Insights

The study reveals that erbB2 (also known as Her2) is crucial for G protein-coupled receptor (GPCR) signaling in heart cells. This finding is important for understanding heart function and potential drug toxicities.

Area of Science:

  • Cardiovascular Biology
  • Molecular Signaling
  • Oncology

Background:

  • erbB2 (Her2) is a receptor kinase with known roles in development and disease, including cardiotoxicity from anti-Her2 cancer therapies.
  • Its function in integrating extracellular signals is established, but its role in G protein-coupled receptor (GPCR) signaling is unknown.
  • GPCR-mediated MAPK pathway activation is vital for maintaining cardiac homeostasis.

Purpose of the Study:

  • To investigate the role of erbB2 in GPCR-mediated MAPK signaling within cardiac myocytes.
  • To determine if erbB2 is essential for the activation of the MAPK pathway by GPCR agonists in the heart.

Main Methods:

  • Utilized wild-type and heart-specific erbB2 mutant mice.
  • Administered GPCR agonists to assess MAPK activation and cardiac function.
  • Performed in vitro studies involving coexpression of erbB2 and GPCRs in heterologous cells.
  • Investigated in vivo immunocomplex formation between erbB2 and GPCRs.

Main Results:

  • erbB2, not EGF receptor, is essential for MAPK activation by various GPCR agonists in cardiac myocytes.
  • erbB2 forms immunocomplexes with GPCRs in vivo and is transactivated upon ligand stimulation in vitro.
  • Coexpression studies confirmed ligand-dependent complex formation and MAPK activation.
  • Heart-specific erbB2 mutants exhibited impaired MAPK activation and cardiac contractility upon GPCR agonist infusion.

Conclusions:

  • erbB2 acts as a coreceptor, essential for GPCR signaling in the heart.
  • This mechanism highlights a critical role for erbB2 in integrating GPCR-mediated signals, impacting cardiac function.
  • The findings suggest that erbB2's involvement in GPCR signaling may extend to other cellular systems.

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