Biased signalling and proteinase-activated receptors (PARs): Targeting inflammatory disease

Hollenberg, M. D., Mihara, K., Polley, D., Suen, J. Y., Han, A., Fairlie, D. P. and Ramachandran, R. (2014) Biased signalling and proteinase-activated receptors (PARs): Targeting inflammatory disease. British Journal of Pharmacology, 171 5: 1180-1194. doi:10.1111/bph.12544


Author Hollenberg, M. D.
Mihara, K.
Polley, D.
Suen, J. Y.
Han, A.
Fairlie, D. P.
Ramachandran, R.
Title Biased signalling and proteinase-activated receptors (PARs): Targeting inflammatory disease
Journal name British Journal of Pharmacology   Check publisher's open access policy
ISSN 0007-1188
1476-5381
Publication date 2014-01-01
Year available 2014
Sub-type Critical review of research, literature review, critical commentary
DOI 10.1111/bph.12544
Volume 171
Issue 5
Start page 1180
End page 1194
Total pages 15
Place of publication Chichester, West Sussex, United Kingdom
Publisher John Wiley and Sons Ltd.
Collection year 2015
Language eng
Subject 3004 Pharmacology
Abstract Although it has been known since the 1960s that trypsin and chymotrypsin can mimic hormone action in tissues, it took until the 1990s to discover that serine proteinases can regulate cells by cleaving and activating a unique four-member family of GPCRs known as proteinase-activated receptors (PARs). PAR activation involves the proteolytic exposure of its N-terminal receptor sequence that folds back to function as a 'tethered' receptor-activating ligand (TL). A key N-terminal arginine in each of PARs 1 to 4 has been singled out as a target for cleavage by thrombin (PARs 1, 3 and 4), trypsin (PARs 2 and 4) or other proteases to unmask the TL that activates signalling via Gq, G i or G12/13. Similarly, synthetic receptor-activating peptides, corresponding to the exposed 'TL sequences' (e.g. SFLLRN -, for PAR1 or SLIGRL - for PAR2) can, like proteinase activation, also drive signalling via Gq, Gi and G12/13, without requiring receptor cleavage. Recent data show, however, that distinct proteinase-revealed 'non-canonical' PAR tethered-ligand sequences and PAR-activating agonist and antagonist peptide analogues can induce 'biased' PAR signalling, for example, via G12/13-MAPKinase instead of Gq-calcium. This overview summarizes implications of this 'biased' signalling by PAR agonists and antagonists for the recognized roles the PARs play in inflammatory settings.
Keyword Activated protein C
Biased signalling
Proteinase activated receptor 2
Protease
Thrombin
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Critical review of research, literature review, critical commentary
Collections: Official 2015 Collection
Institute for Molecular Bioscience - Publications
 
Versions
Version Filter Type
Citation counts: TR Web of Science Citation Count  Cited 46 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 50 times in Scopus Article | Citations
Google Scholar Search Google Scholar
Created: Tue, 18 Mar 2014, 10:22:58 EST by System User on behalf of Institute for Molecular Bioscience