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Related Experiment Videos

Controlling signaling with a specifically designed Gi-coupled receptor

P Coward1, H G Wada, M S Falk

  • 1Gladstone Institute for Cardiovascular Disease, Departments of Medicine and Pharmacology, University of California, San Francisco, CA 94141-9100, USA.

Proceedings of the National Academy of Sciences of the United States of America
|February 21, 1998
PubMed
Summary

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Scientists engineered novel receptors, RASSLs (receptor activated solely by a synthetic ligand), to precisely control G protein signaling. These receptors offer a new method for regulating physiological responses in vivo with synthetic drugs.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Pharmacology

Background:

  • G protein signaling pathways regulate diverse physiological responses.
  • Targeting G protein-coupled receptors (GPCRs) is crucial for therapeutic interventions.
  • Existing GPCR systems often lack specificity and can be activated by endogenous ligands.

Purpose of the Study:

  • To develop engineered GPCRs, termed RASSLs (receptor activated solely by a synthetic ligand), for exclusive response to synthetic ligands.
  • To demonstrate the feasibility of RASSLs for precise in vivo control of G protein signaling.
  • To explore potential applications of RASSLs in cell enrichment and disease modeling.

Main Methods:

  • Engineering of kappa opioid receptors into RASSLs to prevent binding/activation by endogenous opioids.

Related Experiment Videos

  • Utilizing binding and signaling assays to quantify RASSL specificity.
  • Employing high-throughput screening in Chinese hamster ovary K1 cells to assess RASSL response to various ligands.
  • Testing RASSL-mediated cell proliferation in rat-1a cells.

    • Main Results:

    • Developed two prototype RASSLs based on the human kappa opioid receptor with significantly reduced affinity for dynorphin (200-2000 fold).
    • Demonstrated that RASSLs show minimal response to a panel of 21 opioid peptides but retain normal signaling with synthetic drugs like spiradoline.
    • Confirmed RASSL activation by spiradoline induced rat-1a cell proliferation.

    Conclusions:

    • GPCRs can be successfully engineered into RASSLs, enabling synthetic ligand-specific activation.
    • RASSLs provide a novel tool for precise control of G protein signaling in vivo.
    • RASSLs hold promise for applications in cell-based therapies and the creation of advanced animal models for disease research.