{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,4]],"date-time":"2026-07-04T02:14:43Z","timestamp":1783131283030,"version":"3.54.6"},"reference-count":79,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2014,4,11]],"date-time":"2014-04-11T00:00:00Z","timestamp":1397174400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/3.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Protease-activated receptors (PARs) are a family of four G protein-coupled receptors that exhibit increasingly appreciated differences in signaling and regulation  both within and between the receptor class. By nature of their proteolytic self-activation mechanism, PARs have unique processes of receptor activation, \u201cligand\u201d binding, and desensitization\/resensitization. These distinctive aspects have presented both challenges and opportunities in the targeting of PARs for therapeutic benefit\u2014the most notable example of which is inhibition of PAR1 on platelets for the prevention of arterial thrombosis. However, more recent studies have uncovered further distinguishing features of PAR-mediated signaling, revealing mechanisms by which identical proteases elicit distinct effects in the same cell, as well as how distinct proteases produce different cellular consequences via the same receptor. Here we review this differential signaling by PARs, highlight how important distinctions between PAR1 and PAR4 are impacting on the progress of a new class of anti-thrombotic drugs, and discuss how these more recent insights into PAR signaling may present further opportunities for manipulating PAR activation and signaling in the development of novel therapies.<\/jats:p>","DOI":"10.3390\/ijms15046169","type":"journal-article","created":{"date-parts":[[2014,4,11]],"date-time":"2014-04-11T06:03:36Z","timestamp":1397196216000},"page":"6169-6183","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":38,"title":["Differential Signaling by Protease-Activated Receptors: Implications for Therapeutic Targeting"],"prefix":"10.3390","volume":"15","author":[{"given":"Tejminder","family":"Sidhu","sequence":"first","affiliation":[{"name":"Australian Centre for Blood Diseases & Department of Clinical Haematology, Monash University, Melbourne 3004, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shauna","family":"French","sequence":"additional","affiliation":[{"name":"Australian Centre for Blood Diseases & Department of Clinical Haematology, Monash University, Melbourne 3004, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justin","family":"Hamilton","sequence":"additional","affiliation":[{"name":"Australian Centre for Blood Diseases & Department of Clinical Haematology, Monash University, Melbourne 3004, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2014,4,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"690","DOI":"10.1038\/29325","article-title":"A dual thrombin receptor system for platelet activation","volume":"394","author":"Kahn","year":"1998","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"879","DOI":"10.1172\/JCI6042","article-title":"Protease-activated receptors 1 and 4 mediate activation of human platelets by thrombin","volume":"103","author":"Kahn","year":"1999","journal-title":"J. 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