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Related Experiment Videos

How the protease thrombin talks to cells.

S R Coughlin1

  • 1Cardiovascular Research Institute, Department of Medicine, University of California, San Francisco, CA 94143-0130, USA. shaun_coughlin@quickmail.ucsf.edu

Proceedings of the National Academy of Sciences of the United States of America
|September 29, 1999
PubMed
Summary

Thrombin, a protease, acts as a hormone by activating protease-activated receptors (PARs) on cells. This unique activation mechanism requires special cellular trafficking to regulate signaling and maintain cell responsiveness.

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Protease-activated receptors in the cardiovascular system.

Cold Spring Harbor symposia on quantitative biology·2003

Area of Science:

  • Biochemistry
  • Cell Biology
  • Molecular Signaling

Background:

  • Proteases, like thrombin, can function as signaling molecules, regulating cellular activities through G protein-coupled receptors (PARs).
  • Protease-activated receptor 1 (PAR1) is activated by thrombin cleavage, which unmasks a tethered ligand for sustained signaling.

Purpose of the Study:

  • To investigate the unique activation mechanism of PAR1 by thrombin and its implications for cellular signaling.
  • To understand the desensitization and resensitization processes for PAR1 compared to classical G protein-coupled receptors.

Main Methods:

  • Analysis of PAR1 activation by thrombin, including receptor cleavage and tethered ligand formation.
  • Investigation of receptor trafficking and localization in endothelial cells and fibroblasts after PAR1 activation.

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  • Studies using knockout mice, receptor-activating peptides, and blocking antibodies to define PAR roles in vivo.

    • Main Results:

    • PAR1 activation by thrombin involves irreversible proteolytic cleavage, unlike reversible ligand binding in classical GPCRs.
    • Activated PAR1 internalizes and sorts to lysosomes, a distinct pathway from the recycling of classical GPCRs.
    • This lysosomal trafficking is crucial for terminating thrombin signaling, with intracellular receptor pools maintaining cell surface availability.

    Conclusions:

    • Cells employ unique trafficking mechanisms to manage signaling from proteases like thrombin acting through PARs.
    • The distinct endosomal sorting of activated PAR1 is essential for regulating thrombin-mediated cellular responses.
    • Understanding PAR signaling is critical for defining roles in various physiological processes, with ongoing research in vivo.