Differential signaling by protease-activated receptors: implications for therapeutic targeting

Tejminder Sidhu, Shauna French, Justin Raymond Hamilton

Research output: Contribution to journalArticleResearchpeer-review

Abstract

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, ligand binding, and desensitization/resensitization. These distinctive aspects have presented both challenges and opportunities in the targeting of PARs for therapeutic benefit-the 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. ? 2014 by the authors; licensee MDPI, Basel, Switzerland.
Original languageEnglish
Pages (from-to)6169 - 6183
Number of pages15
JournalInternational Journal of Molecular Sciences
Volume15
Issue number4
DOIs
Publication statusPublished - 2014

Cite this

@article{c73ddf13d7be4e7988f2493823308ea7,
title = "Differential signaling by protease-activated receptors: implications for therapeutic targeting",
abstract = "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, ligand binding, and desensitization/resensitization. These distinctive aspects have presented both challenges and opportunities in the targeting of PARs for therapeutic benefit-the 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. ? 2014 by the authors; licensee MDPI, Basel, Switzerland.",
author = "Tejminder Sidhu and Shauna French and Hamilton, {Justin Raymond}",
year = "2014",
doi = "10.3390/ijms15046169",
language = "English",
volume = "15",
pages = "6169 -- 6183",
journal = "International Journal of Molecular Sciences",
issn = "1422-0067",
publisher = "MDPI AG",
number = "4",

}

Differential signaling by protease-activated receptors: implications for therapeutic targeting. / Sidhu, Tejminder; French, Shauna; Hamilton, Justin Raymond.

In: International Journal of Molecular Sciences, Vol. 15, No. 4, 2014, p. 6169 - 6183.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Differential signaling by protease-activated receptors: implications for therapeutic targeting

AU - Sidhu, Tejminder

AU - French, Shauna

AU - Hamilton, Justin Raymond

PY - 2014

Y1 - 2014

N2 - 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, ligand binding, and desensitization/resensitization. These distinctive aspects have presented both challenges and opportunities in the targeting of PARs for therapeutic benefit-the 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. ? 2014 by the authors; licensee MDPI, Basel, Switzerland.

AB - 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, ligand binding, and desensitization/resensitization. These distinctive aspects have presented both challenges and opportunities in the targeting of PARs for therapeutic benefit-the 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. ? 2014 by the authors; licensee MDPI, Basel, Switzerland.

UR - http://www.mdpi.com/1422-0067/15/4/6169

U2 - 10.3390/ijms15046169

DO - 10.3390/ijms15046169

M3 - Article

VL - 15

SP - 6169

EP - 6183

JO - International Journal of Molecular Sciences

JF - International Journal of Molecular Sciences

SN - 1422-0067

IS - 4

ER -