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Review ArticleReview

Proteinase-Activated Receptors

Scott R. Macfarlane, Michael J. Seatter, Toru Kanke, Gary D. Hunter and Robin Plevin
Pharmacological Reviews June 2001, 53 (2) 245-282;
Scott R. Macfarlane
Department of Physiology and Pharmacology, University of Strathclyde, Strathclyde Institute for Biomedical Sciences, Glasgow, United Kingdom
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Michael J. Seatter
Department of Physiology and Pharmacology, University of Strathclyde, Strathclyde Institute for Biomedical Sciences, Glasgow, United Kingdom
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Toru Kanke
Department of Physiology and Pharmacology, University of Strathclyde, Strathclyde Institute for Biomedical Sciences, Glasgow, United Kingdom
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Gary D. Hunter
Department of Physiology and Pharmacology, University of Strathclyde, Strathclyde Institute for Biomedical Sciences, Glasgow, United Kingdom
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Robin Plevin
Department of Physiology and Pharmacology, University of Strathclyde, Strathclyde Institute for Biomedical Sciences, Glasgow, United Kingdom
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Abstract

Proteinase-activated receptors are a recently described, novel family of seven-transmembrane G-protein-coupled receptors. Rather then being stimulated through ligand receptor occupancy, activation is initiated by cleavage of the N terminus of the receptor by a serine protease resulting in the generation of a new tethered ligand that interacts with the receptor within extracellular loop-2. To date, four proteinase-activated receptors (PARs) have been identified, with distinct N-terminal cleavage sites and tethered ligand pharmacology. In addition to the progress in the generation of PAR-1 antagonists, we describe the role of thrombin in such processes as wound healing and the evidence implicating PAR-1 in vascular disorders and cancer. We also identify advances in the understanding of PAR-1-mediated intracellular signaling and receptor desensitization. The cellular functions, signaling events, and desensitization processes involved in PAR-2 activation are also assessed. However, other major aspects of PAR-2 are highlighted, in particular the ability of several serine protease enzymes, in addition to trypsin, to function as activators of PAR-2. The likely physiological and pathophysiological roles for PAR-2 in skin, intestine, blood vessels, and the peripheral nervous system are considered in the context of PAR-2 activation by multiple serine proteases. The recent discovery of PAR-3 and PAR-4 as additional thrombin-sensitive PARs further highlights the complexity in assessing the effects of thrombin in several different systems, an issue that remains to be fully addressed. These discoveries have also highlighted possible PAR–PAR interactions at both functional and molecular levels. The future identification of other PARs and their modes of activation are an important future direction for this expanding field of study.

Footnotes

  • ↵1 Address for correspondence: Robin Plevin, Department of Physiology and Pharmacology, University of Strathclyde, Strathclyde Institute for Biomedical Sciences, 27 Taylor St., Glasgow G4ONR, UK. E-mail: r.plevin{at}strath.ac.uk

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In this issue

Pharmacological Reviews: 53 (2)
Pharmacological Reviews
Vol. 53, Issue 2
1 Jun 2001
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Review ArticleReview

Proteinase-Activated Receptors

Scott R. Macfarlane, Michael J. Seatter, Toru Kanke, Gary D. Hunter and Robin Plevin
Pharmacological Reviews June 1, 2001, 53 (2) 245-282;

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Review ArticleReview

Proteinase-Activated Receptors

Scott R. Macfarlane, Michael J. Seatter, Toru Kanke, Gary D. Hunter and Robin Plevin
Pharmacological Reviews June 1, 2001, 53 (2) 245-282;
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  • Article
    • Abstract
    • I. Introduction
    • II. Historical Perspectives—Cellular Effects of Thrombin and the Cloning of the Thrombin Receptor, Proteinase-Activated Receptor-1
    • III. Pharmacology of Proteinase-Activated Receptor-1
    • IV. Functional Responses to Proteinase-Activated Receptor-1 Activation
    • V. Proteinase-Activated Receptor-1-Mediated Cellular Signaling
    • VI. Desensitization of Proteinase-Activated Receptor-1
    • VII. Cloning of Proteinase-Activated Receptor-2
    • VIII. Functional Responses to Proteinase-Activated Receptor-2 Activation
    • IX. Endogenous Activators of Proteinase-Activated Receptor-2
    • X. Pharmacology of Proteinase-Activated Receptor-2
    • XI. Proteinase-Activated Receptor-2-Mediated Intracellular Signaling
    • XII. Proteinase-Activated Receptor-2 Desensitization
    • XIII. Identification and Function of Proteinase-Activated Receptor-3 and Proteinase-Activated Receptor-4
    • XIV. Functional and Molecular Interactions Between Proteinase-Activated Receptors
    • XV. Proteinase-Activated Receptors as Therapeutic Targets in Disease States
    • XVI. Future Perspectives
    • Acknowledgments
    • Footnotes
    • Abbreviations
    • References
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