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Proteinase-activated receptors in the nervous system

Nature Reviews Neuroscience volume 4, pages 981–990 (2003)Cite this article

Key Points

  • Proteinase-activated receptors (PARs) are a class of G-protein-coupled receptors, the main peculiarity of which is that they are activated by proteolytic cleavage. Four PARs have been cloned so far, and all of them are expressed in the nervous system.

  • Several proteinases that are present in the nervous system — such as thrombin and trypsin — can activate PARs. Peptides that mimic the amino-terminal sequence that results from proteolytic cleavage can act as receptor agonists, and are a key asset for pharmacological studies.

  • Receptor cleavage leads to the activation of different kinds of G proteins, including G12/13, Go/i and Gq, and signalling through the phospholipase C, mitogen-activated protein kinase, and Src kinase pathways, among others.

  • PAR activation has several physiological effects on nerve cells and glia. PARs can affect the proliferation of cells, neuritic morphology and synaptic plasticity. In the periphery, PARs might also be involved in neurogenic inflammation, pain and nerve regeneration.

  • PARs seem to affect neuronal survival, but their effects are complex, as they can be neuroprotective or lead to cell death. Similarly, our understanding of the involvement of PARs in neurodegenerative disorders is still incomplete — these receptors have been implicated in Alzheimer's disease, HIV-associated dementia, multiple sclerosis and other disorders.

  • In addition to discovering which additional brain-expressed proteinases can activate PARs, it will be important to define their potential as drug targets in the different neurological conditions in which they might be involved.

Abstract

Recent data point to important roles for proteinases and their cognate proteinase-activated receptors (PARs) in the ontogeny and pathophysiology of the nervous system. PARs are a family of G-protein-coupled receptors that can affect neural cell proliferation, morphology and physiology. PARs also have important roles in neuroinflammatory and degenerative diseases such as human immunodeficiency virus-associated dementia, Alzheimer's disease and pain. These receptors might also influence the pathogenesis of stroke and multiple sclerosis, conditions in which the blood–brain barrier is disrupted. The diversity of effects of PARs on neural function and their widespread distribution in the nervous system make them attractive therapeutic targets for neurological disorders. Here, we review the roles of PARs in the central and peripheral nervous systems during health and disease, with a focus on neuroinflammatory and degenerative disorders.

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Figure 1: The structure and function of proteinase-activated receptors.
Figure 2: PAR1 signalling mechanisms.
Figure 3: Activation and expression of proteinase-activated receptors (PARs) in the central nervous system.

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Acknowledgements

F.N. holds a scholarship from the Iranian Ministry of Health and Medical Education. N.V. is a Canadian Institutes of Health Research/NicOx Investigator. C.P. is an Alberta Heritage Foundation for Medical Research Scholar/Canadian Institutes of Health Research Investigator and holds the Strafford Foundation Chair in Alzheimer's Disease Research.

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Authors and Affiliations

  1. Neuroscience, University of Calgary, Alberta, T2N 4N1, Canada

    Farshid Noorbakhsh & Christopher Power

  2. Mucosal Inflammation Research Groups, University of Calgary, Alberta, T2N 4N1, Canada

    Nathalie Vergnolle & Morley D. Hollenberg

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

    Christopher Power

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

    Nathalie Vergnolle & Morley D. Hollenberg

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

    Morley D. Hollenberg

  6. Department of Immunology, Tehran University of Medical Sciences, Iran

    Farshid Noorbakhsh

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  1. Farshid Noorbakhsh
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  2. Nathalie Vergnolle
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  3. Morley D. Hollenberg
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Correspondence to Christopher Power.

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DATABASES

LocusLink

CGRP

MMP12

Substance P

OMIM

Cathepsin G

GAP43

Mast-cell tryptase

MS

PAR1

PAR2

PAR3

PAR4

Thrombin

Trypsin

Glossary

EXPRESSION CLONING

A cloning strategy that is based on the transfection of complementary DNAs such that functional proteins are expressed, followed by screening of the functional activity of the gene of interest.

HYDROPATHY ANALYSIS

Analysis that allows the visualization of hydrophobicity patterns in a peptide sequence, and is particularly useful in determining the membrane-spanning regions of proteins. Obtaining a hydropathy plot requires the use of a hydropathy scale that is based on the hydrophobic and hydrophilic properties of the 20 amino acids. A moving window determines the summed hydropathy at each point in the sequence, and this value is then plotted against the amino-acid positions.

ANION-BINDING EXOSITE

The non-catalytic substrate-binding site of thrombin. Each thrombin molecule has two anion-binding exosites.

EXPRESSED SEQUENCE TAGS

Short (200–500 base pairs) DNA sequences that represent the sequences expressed in an organism under a given condition. They are generated from the 3′- and 5′-ends of randomly selected complementary DNA clones. The purpose of expressed sequence tag sequencing is to scan for all the protein-coding genes, and to provide a tag for each gene in the genome.

MITOGEN-ACTIVATED PROTEIN KINASE CASCADE

A signalling cascade that relays signals from the plasma membrane to the nucleus. Mitogen-activated protein (MAP) kinases, which catalyse the last step in the pathway, are activated by a wide range of proliferation- or differentiation-inducing signals. Extracellular signal-regulated kinases are among the best-characterized MAP kinases.

SRC

A cytoplasmic tyrosine kinase that was first identified as a transforming oncogene in an avian retrovirus. This kinase is the prototypical kinase from which Src-homology regions were first described.

RHO GTPASES

A family of proteins that are related to the product of the Ras oncogene and are involved in controlling the polymerization of actin.

LONG-TERM POTENTIATION

An enduring increase in the amplitude of excitatory postsynaptic potentials as a result of high-frequency (tetanic) stimulation of afferent pathways. It is measured both as the amplitude of excitatory postsynaptic potentials and as the magnitude of the postsynaptic-cell population spike. Long-term potentiation is most often studied in the hippocampus, and is often considered to be the cellular basis of learning and memory in vertebrates.

OEDEMA

The presence of abnormally large amounts of fluid in the intercellular spaces.

HYPERALGESIA

The perception of a stimulus as more painful than when previously experienced.

ALLODYNIA

The perception of a stimulus as painful when previously the same stimulus was reported to be non-painful.

ATOPIC DERMATITIS

A common form of eczema that is often accompanied by allergies and asthma.

VANILLOID RECEPTORS

A family of receptors that are involved in the perception of hot temperature. The first member of the family was identified owing to its sensitivity to capsaicin — the hot component of chili peppers.

WOBBLER MOUSE

A mutant mouse that shows motor neuron degeneration and astrocyte reactivity in the spinal cord, and defects in spermatogenesis. The mutant gene has not been identified.

CD40

A molecule that is present in B lymphocytes, which partly triggers their growth by binding to the CD40 ligand on the surface of activated helper T cells.

ISCHAEMIC PRECONDITIONING

An adaptive response of tissue that has been reversibly affected by an episode of ischaemia such that its resistance to subsequent ischaemic episodes is increased.

MYELIN PALLOR

Abnormal appearance of white matter in histological sections as a result of disrupted blood–brain barrier integrity.

EXTRAVASATION

Refers to the leakage of plasma and plasma proteins from post-capillary venules — recognized as oedema.

CD4

A receptor present in a subset of T lymphocytes that are essential for turning on antibody production, activating cytotoxic T cells and initiating other immune responses.

EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS

A rodent model of multiple sclerosis that is characterized by episodes of spasticity and tremor.

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Noorbakhsh, F., Vergnolle, N., Hollenberg, M. et al. Proteinase-activated receptors in the nervous system. Nat Rev Neurosci 4, 981–990 (2003). https://doi.org/10.1038/nrn1255

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