2012
DOI: 10.1111/j.1476-5381.2011.01610.x
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Modulating human proteinase activated receptor 2 with a novel antagonist (GB88) and agonist (GB110)

Abstract: BACKGROUND AND PURPOSEMany cells express proteinase activated receptor 2 (PAR2) on their plasma membrane. PAR2 is activated by proteolytic enzymes, such as trypsin and tryptase that cleave the receptor N-terminus, inititating signalling to intracellular G proteins. Studies on PAR2 have relied heavily upon activating effects of proteases and peptide agonists that lack stability and bioavailability in vivo. EXPERIMENTAL APPROACHA novel small molecule agonist GB110 and an antagonist GB88 were characterized in vit… Show more

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Cited by 108 publications
(168 citation statements)
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“…We first determined whether Cat-S cleaved a decapeptide in which the P2, P1, and P1Ј positions were substituted: V 55 3 S, E 56 3 P, and T 57 3 K ( 52 GVTSPKVFSVD 62 ). As expected, Cat-S was unable to cleave this peptide at concentration up to 880 M (Fig.…”
Section: Cat-s Cleaves Par 2 Expressed In Hek Cells But Does Notmentioning
confidence: 99%
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“…We first determined whether Cat-S cleaved a decapeptide in which the P2, P1, and P1Ј positions were substituted: V 55 3 S, E 56 3 P, and T 57 3 K ( 52 GVTSPKVFSVD 62 ). As expected, Cat-S was unable to cleave this peptide at concentration up to 880 M (Fig.…”
Section: Cat-s Cleaves Par 2 Expressed In Hek Cells But Does Notmentioning
confidence: 99%
“…In experiments in HEK293 cells expressing PAR 2 with N-terminal Flag and C-terminal HA11 epitopes, we observed that Cat-S removed the extracellular Flag epitope, which indicates that Cat-S can cleave intact PAR 2 at the cell surface as well as receptor fragments. To ascertain the importance of cleavage at the E 56 2T 57 for Cat-S activation of PAR 2 , we studied the capacity of Cat-S to cleave and activate a mutant receptor in which the P2, P1 and P1Ј positions were replaced: V 55 Cat-S cleaves within the N terminus of PAR 2 is consistent with the known requirements for Cat-S substrate recognition (56,57). Aliphatic residues at the P2 position, including valine and leucine, direct Cat-S selectivity.…”
mentioning
confidence: 99%
“…186−188 It has proven to be a very useful probe for studying effects of PAR2 antagonism in a range of in vivo disease models, including rat paw edema, colitis, arthritis, and diet-induced metabolic dysfunction. Antagonist 22 (5−10 mg/kg, po) attenuated PAR2, but not PAR1, agonistinduced paw edema and acute inflammation, 187 as well as inhibited collagen-induced arthritis in rats. 188 It also inhibited PAR2 agonist-induced acute colonic inflammation and chronic TNBS-induced colitis in rats at 10 mg kg…”
Section: ■ Par2 Antagonistsmentioning
confidence: 99%
“…Interestingly, 22 was equipotent (IC 50 1 μM, iCa 2+ ) against all three types of PAR2 agonist in seven different human cell types. 187 Compound 22 was a surmountable and competitive antagonist of 2f-LIGRLO-NH 2 (with a Schild plot slope being unity) but a competitive yet insurmountable antagonist of agonist 16. 187 This suggested that 22, 16, and 2f-LIGRLO-NH 2 bind at the same, or an overlapping, site on PAR2.…”
Section: ■ Par2 Antagonistsmentioning
confidence: 99%
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