In:
Journal of Peptide Science, Wiley, Vol. 13, No. 12 ( 2007-12), p. 856-861
Abstract:
Protease‐activated receptor 2 (PAR 2 ) is a G protein‐coupled cell surface receptor for trypsin‐like enzymes. Proteolytic cleavage at a specific site in the extracellular N ‐terminus exposes a receptor‐activating sequence, the ‘tethered ligand’, which binds intramolecularly to initiate receptor signalling. Peptide or small molecule agonists for PAR 2 , devoid of the non‐specific and proteolytic effects of enzyme activators, may be promising therapeutic agents for proliferative and inflammatory diseases reportedly mediated by PAR 2 . Synthetic hexapeptides that correspond to the native tethered ligand of human or rodent PAR 2 (SLIGKV and SLIGRL, respectively) can activate the receptor independently of proteolytic cleavage; however, known peptide agonists have much lower potency compared to protease‐mediated activation. Here, we investigated the agonist activity of 94 hepta and octapeptide derivatives of the human and rodent PAR 2 ‐tethered ligand sequences in human airway epithelial (A549) cells which endogenously express PAR 2 . Thirty synthetic peptides were found to be as potent as or more potent than SLIGRL on the basis of intracellular Ca 2+ responses. The more active peptide agonists were also examined for agonist cross‐reactivity at PAR 1 in Chinese Hamster Ovary (CHO) cells that endogenously express functional PAR 1 but not PAR 2 . Two potent and PAR 2 ‐selective agonists were further examined for their capacity to relax phenylephrine‐contracted rat aortic rings. Our findings reveal an important role for carboxyl extensions to native PAR 2 activating peptides in potentiating agonist activity. Copyright © 2007 European Peptide Society and John Wiley & Sons, Ltd.
Type of Medium:
Online Resource
ISSN:
1075-2617
,
1099-1387
Language:
English
Publisher:
Wiley
Publication Date:
2007
detail.hit.zdb_id:
1491819-5
SSG:
12
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