Structure, function and pathophysiology of protease activated receptors

Authors

Mark N. Adams, Mater Medical Research Institute
Rithwik Ramachandran, University of Calgary
Mei Kwan Yau, The University of Queensland
Jacky Y. Suen, The University of Queensland
David P. Fairlie, The University of Queensland
Morley D. Hollenberg, University of Calgary
John D. Hooper, Mater Medical Research Institute

Document Type

Article

Publication Date

1-1-2011

Journal

Pharmacology and Therapeutics

Volume

130

Issue

3

First Page

248

Last Page

282

URL with Digital Object Identifier

10.1016/j.pharmthera.2011.01.003

Abstract

Discovered in the 1990s, protease activated receptors1 (PARs) are membrane-spanning cell surface proteins that belong to the G protein coupled receptor (GPCR) family. A defining feature of these receptors is their irreversible activation by proteases; mainly serine. Proteolytic agonists remove the PAR extracellular amino terminal pro-domain to expose a new amino terminus, or tethered ligand, that binds intramolecularly to induce intracellular signal transduction via a number of molecular pathways that regulate a variety of cellular responses. By these mechanisms PARs function as cell surface sensors of extracellular and cell surface associated proteases, contributing extensively to regulation of homeostasis, as well as to dysfunctional responses required for progression of a number of diseases. This review examines common and distinguishing structural features of PARs, mechanisms of receptor activation, trafficking and signal termination, and discusses the physiological and pathological roles of these receptors and emerging approaches for modulating PAR-mediated signaling in disease. © 2011 Elsevier Inc.