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Targeting proteinase-activated receptors: therapeutic potential and challenges

Nature Reviews Drug Discovery volume 11, pages 69–86 (2012)Cite this article

Subjects

Key Points

  • Proteinase-activated receptors are seven-transmembrane G protein-coupled receptors with an unusual mechanism of activation involving the proteolytic unmasking of a tethered ligand.

  • Proteinase-activated receptors have been established as therapeutic targets in cardiovascular, musculoskeletal, gastrointestinal, respiratory and central nervous system pathologies.

  • Proteinase-activated receptors can be activated by multiple proteinases, and can exhibit so-called biased signalling, which is dependent on the agonist that is stimulating the receptor and on the membrane localization of the receptor.

  • Proteinase-activated receptors can be targeted for therapy using multiple strategies that include blocking the proteolytic cleavage of the receptor, interdicting the interaction between the tethered ligand and the receptor, or modulating intracellular interactions between the receptor and effectors.

Abstract

Proteinase-activated receptors (PARs), a family of four seven-transmembrane G protein-coupled receptors, act as targets for signalling by various proteolytic enzymes. PARs are characterized by a unique activation mechanism involving the proteolytic unmasking of a tethered ligand that stimulates the receptor. Given the emerging roles of these receptors in cancer as well as in disorders of the cardiovascular, musculoskeletal, gastrointestinal, respiratory and central nervous system, PARs have become attractive targets for the development of novel therapeutics. In this Review we summarize the mechanisms by which PARs modulate cell function and the roles they can have in physiology and diseases. Furthermore, we provide an overview of possible strategies for developing PAR antagonists.

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Figure 1: Mechanism of proteinase-activated receptor activation.
Figure 2: Intracellular trafficking of activated proteinase-activated receptors.
Figure 3: Proteinase-activated receptor modulators.
Figure 4: Important structural motifs regulating PAR function and strategies for modulating PARs.

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Acknowledgements

We acknowledge support from the Canadian Institutes of Health Research (M.D.H.), The Alberta Heritage Foundation for Medical Research (now known as Alberta Innovates Health Solutions; postdoctoral fellowship for R.R.) and the US National Institutes of Health (K.D.). We are indebted to the three reviewers for their insightful suggestions that have helped to clarify the text of this Review.

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Authors and Affiliations

  1. Department of Physiology and Pharmacology, Faculty of Medicine, University of Calgary, Alberta, T2N 4N1, Canada

    Rithwik Ramachandran, Farshid Noorbakhsh & Morley D. Hollenberg

  2. Department of Immunology, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, 14176, Iran

    Farshid Noorbakhsh

  3. University of California Riverside, 900 University Ave., Riverside, 92521, California, USA

    Kathryn DeFea

  4. Department of Medicine, Faculty of Medicine, University of Calgary, Alberta, T2N 4N1, Canada

    Morley D. Hollenberg

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  1. Rithwik Ramachandran
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  2. Farshid Noorbakhsh
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  3. Kathryn DeFea
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Correspondence to Rithwik Ramachandran or Morley D. Hollenberg.

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Glossary

Proteinases

Also known as proteases. Enzymes that catalyse the hydrolysis of peptide bonds. For peptide bond hydrolysis by serine proteinases, the amino acid serine forms a key transition-state intermediate within the catalytic triad, along with histidine and aspartic acid.

G protein-coupled receptors

Putative seven-transmembrane-spanning receptors that act as a GDP–GTP exchange factors for a class of guanine nucleotide-binding signal-transducing G protein heterotrimers (α, β or γ).

Antagonists

Compounds that bind to receptors to inhibit signalling caused by the binding of an endogenous ligand to the receptor. The term can be subcategorized to describe neutral antagonists, partial agonists and inverse agonists.

Agonists

Ligands that activate cell signalling following receptor binding to stimulate either complete or restricted cell responses that are dependent on their ability to drive receptor interactions with multiple signal effectors.

Tethered ligand

A proteolytically revealed extracellular amino-terminal proteinase-activated receptor sequence that, while remaining attached to the receptor carboxy-terminal sequence, can bind to other receptor extracellular domains to initiate cell signalling.

G protein

A heterotrimeric protein, consisting of α-, β- and γ-subunits, that has GTPase activity. Exchange of GDP for GTP triggers the activity of membrane-localized signal effectors such as adenylyl cyclase, and the G protein is recycled to its ground state as GTP is hydrolysed to GDP.

β-arrestin

A multifunctional adaptor protein that is important in regulating desensitization and signalling by seven-transmembrane G protein-coupled receptors and other transmembrane receptors.

Floating or 'mobile' receptor hypothesis

A model of receptor function proposing that a receptor's mobility along with the agonist-mediated changes in its conformation can promote receptor interactions with multiple effectors to trigger a complex array of effector-driven cell responses.

Tissue factor

A cell surface glycoprotein (also termed coagulation factor III) that forms a high-affinity complex with factor VIIa. In turn, the tissue factor–factor VIIa–factor Xa serine proteinase complex comprises the 'extrinsic coagulation pathway' generating thrombin and also activating the proteinase-activated receptors.

Factor VIIa

This activated form of the vitamin K-dependent serine proteinase coagulation factor VII, bound to tissue factor, activates coagulation factor X (to factor Xa) that in turn converts prothrombin to thrombin.

Thrombus

A blood clot of platelets, fibrin and entrapped erythrocytes, generated by the coagulation cascade in a blood vessel or a cardiac cavity. The thrombus can cause blood vessel occlusion, thereby hindering blood flow.

Ussing chamber

Invented by Hans Ussing in the 1950s. A two-chamber apparatus that measures current flow across an epithelial tissue or cultured cell monolayer, supported in the middle on a semi-permeable membrane. The short-circuit current required to cancel the voltage difference between the two chambers represents the net ion transport across the sample.

Pepducin

An N-palmitoylated cell-permeable peptide derived from sequences of the intracellular domain of G protein-coupled receptors (GPCRs) that is able to mimic the intracellular domains of a receptor to interdict the binding of a GPCR with its signal-transducing effectors.

Caveolae

Caveolin-rich 'cave-like' subdomains within lipid rafts of the plasma membrane that serve as locales for subsets of membrane-associated signalling effectors.

Biased agonists

Ligands that result in the activation of a selected subset of known available signalling pathways that are activated by the receptor.

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Ramachandran, R., Noorbakhsh, F., DeFea, K. et al. Targeting proteinase-activated receptors: therapeutic potential and challenges. Nat Rev Drug Discov 11, 69–86 (2012). https://doi.org/10.1038/nrd3615

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