2-Furoyl-LIGRLO-amide: A Potent and Selective Proteinase-Activated Receptor 2 Agonist

McGuire, John J.; Saifeddine, Mahmoud; Triggle, Chris R.; Sun, Kimberly; Hollenberg, Morley D.

doi:10.1124/jpet.103.064584

Cited by 122 publications

(132 citation statements)

References 17 publications

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“…3B) (28). Consistent with this observation, an independent study also described a similar modified peptide, 2-furoyl-LIGRLO-NH 2 , as a potent PAR-2-activating peptide (29). It is not clear whether the addition of C-terminal ornithine alters the PAR-2 agonistic activity; nevertheless, it is clear that 2-furoyl peptides are the most potent agonistics currently available, which are useful in for evaluating PAR-2 function.…”

Section: Par-2 Agonists and Antagonistssupporting

confidence: 52%

Physiology and Pathophysiology of Proteinase-Activated Receptors (PARs): PAR-2 as a Potential Therapeutic Target

et al. 2005

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Abstract. PAR-2 is the second member of the family of proteinase-activated receptors activated by trypsin, tryptase, and several other serine proteinases. In order to evaluate the therapeutic potential for PAR-2, we have performed studies on PAR-2-mediated signal transduction and investigated the effects of PAR-2 gene deficiency in disease models. In addition to the Gprotein-coupled receptor-mediated common signal transduction pathways, inositol 1,4,5-trisphosphate production and mobilization of Ca

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Section: Par-2 Agonists and Antagonistssupporting

confidence: 52%

Physiology and Pathophysiology of Proteinase-Activated Receptors (PARs): PAR-2 as a Potential Therapeutic Target

et al. 2005

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“…We suspect that two factors may contribute to this difference. First, 2-Furoyl-LIGRLO-Amide is a new and potent PAR2 agonist (19) that may induce a stronger activation response than that induced by mast cell tryptase. Second, perfusion with exogenous PAR2 agonist may be equivalent to a higher concentration of endogenous tryptase that would reach the sensory afferent nerve endings after mast cell activation.…”

Section: Discussionmentioning

confidence: 99%

TRPA1 in mast cell activation-induced long-lasting mechanical hypersensitivity of vagal afferent C-fibers in guinea pig esophagus

Gao

Peterson³

et al. 2009

American Journal of Physiology-Gastrointestinal and Liver Physi

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Yu S, Gao G, Peterson BZ, Ouyang A. TRPA1 in mast cell activation-induced long-lasting mechanical hypersensitivity of vagal afferent C-fibers in guinea pig esophagus. Am J Physiol Gastrointest Liver Physiol 297: G34 -G42, 2009. First published May 7, 2009 doi:10.1152/ajpgi.00068.2009.-Sensitization of esophageal sensory afferents by inflammatory mediators plays an important role in esophageal nociception. We have shown esophageal mast cell activation induces long-lasting mechanical hypersensitivity in vagal nodose C-fibers. However, the roles of mast cell mediators and downstream ion channels in this process are unclear. Mast cell tryptase via protease-activated receptor 2 (PAR2)-mediated pathways sensitizes sensory nerves and induces hyperalgesia. Transient receptor potential A1 (TRPA1) plays an important role in mechanosensory transduction and nociception. Here we tested the hypothesis that mast cell activation via a PAR2-dependent mechanism sensitizes TRPA1 to induce mechanical hypersensitivity in esophageal vagal C-fibers. The expression profiles of PAR2 and TRPA1 in vagal nodose ganglia were determined by immunostaining, Western blot, and RT-PCR. Extracellular recordings from esophageal nodose neurons were performed in ex vivo guinea pig esophageal-vagal preparations. Action potentials evoked by esophageal distention and chemical perfusion were compared. Both PAR2 and TRPA1 expressions were identified in vagal nodose neurons by immunostaining, Western blot, and RT-PCR. Ninety-one percent of TRPA1-positive neurons were of small and medium diameters, and 80% coexpressed PAR2. Esophageal mast cell activation significantly enhanced the response of nodose C-fibers to esophageal distension (mechanical hypersensitivity). This was mimicked by PAR2-activating peptide, which sustained for 90 min after wash, but not by PAR2 reverse peptide. TRPA1 inhibitor HC-030031 pretreatment significantly inhibited mechanical hypersensitivity induced by either mast cell activation or PAR2 agonist. Collectively, our data provide new evidence that sensitizing TRPA1 via a PAR2-dependent mechanism plays an important role in mast cell activationinduced mechanical hypersensitivity of vagal nodose C-fibers in guinea pig esophagus. visceral afferent; sensitization; nociception; protease-activated receptor 2; transient receptor potential A1 ABNORMAL ESOPHAGEAL SENSATIONS are generated from sensory afferent nerve endings in the wall of the esophagus and transmitted to the central nervous system by both spinal (27, 31) and vagal (7,25,30,38) pathways. Esophageal sensory afferent nerves usually are polymodal with their cell bodies situated in either dorsal root ganglion (DRG) or nodose/jugular ganglia (21). A subtype of these afferent nerves, nociceptive afferent, can innervate noxious mechanical, chemical, and thermal stimuli to induce nociception (31,36,37). Under certain conditions, such as tissue damage or inflammation, these processes could be enhanced by peripheral and/or central sensitization and result in esophageal hyperalgesia (14,...

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“…It is important that synthetic peptides that correspond to the tethered ligand sequence can be used to activate the receptor in the absence of receptor cleavage. For PAR 2 , these include SLIGRL-NH 2 and 2-furoyl-LIGRLO-NH 2 (Kawabata et al, 2004;McGuire et al, 2004).…”

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confidence: 99%

Prostaglandin E₂Derived from Cyclooxygenases 1 and 2 Mediates Intestinal Epithelial Ion Transport Stimulated by the Activation of Protease-Activated Receptor 2

Merwe

Ohland²,

Hirota³

et al. 2009

J Pharmacol Exp Ther

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Proteinase-activated receptor (PAR) 2 is activated by trypsinlike serine proteinases and has been implicated in intestinal inflammation. However, its role in the regulation of intestinal mucosal function remains unclear. Using the intestinal epithelial cell line, SCBN, we have studied the stimulus-secretion coupling mechanisms of PAR 2 -induced epithelial chloride transport, focusing on cyclooxygenase (COX)-1 and COX-2 activities and prostaglandin (PG) E 2 secretion. SCBN monolayers were grown on Snapwell supports, mounted in modified Ussing chambers, and exposed to the activating peptide, SLIGRL-NH 2 (50 M), to activate PAR 2 . Pretreatment with inhibitors of cytosolic PLA 2 (cPLA 2 ) (AACOCF3, arachidonyltrifluoromethyl ketone), COX-1 [SC560, 5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole], and COX-2 (celecoxib) resulted in a significant concentration-dependent attenuation of PAR 2 -induced changes in short-circuit current. Immunoblot analysis showed a PAR 2 -induced increase in cPLA 2 phosphorylation that was blocked by the mitogen-activated protein kinase kinase inhibitor, PD98059 [2-(2-amino-3methoxyphenyl)-4H-1benzopyran-4-one, C 16 H 13 NO 3 ], and the pan-protein kinase C inhibitor, GFX (bisindolylmaleimide). PAR 2 stimulation also resulted in a large increase in the production of PGE 2 as determined by enzyme-linked immunosorbent assay and was also blocked by PD98059 and GFX. Immunofluorescence and immunoblot analysis determined that EP2 and EP4 are expressed at the basolateral membrane of SCBN cells. Through the use of selective inhibitors (EP2, AH6809 [6-isopropoxy-9-oxoxanthene-2-carboxylic acid]; EP4, GW627368X [N-{2[4,9-diethoxy-1-oxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl)phenyl] acetyl}benzene sulphonamide]), it was found that both EP2 and EP4 were involved in mediating the PAR 2 -induced chloride secretory response. We conclude that basolateral PAR 2 activation induces epithelial chloride secretion that is mediated by cPLA 2 , COX-1, COX-2, and the subsequent release of PGE 2 . The production of PGE 2 results in an autocrine secretory response that is dependent on basolateral EP2 and EP4 receptors.

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2-Furoyl-LIGRLO-amide: A Potent and Selective Proteinase-Activated Receptor 2 Agonist

Cited by 122 publications

References 17 publications

Physiology and Pathophysiology of Proteinase-Activated Receptors (PARs): PAR-2 as a Potential Therapeutic Target

Physiology and Pathophysiology of Proteinase-Activated Receptors (PARs): PAR-2 as a Potential Therapeutic Target

TRPA1 in mast cell activation-induced long-lasting mechanical hypersensitivity of vagal afferent C-fibers in guinea pig esophagus

Prostaglandin E₂Derived from Cyclooxygenases 1 and 2 Mediates Intestinal Epithelial Ion Transport Stimulated by the Activation of Protease-Activated Receptor 2

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2-Furoyl-LIGRLO-amide: A Potent and Selective Proteinase-Activated Receptor 2 Agonist

Cited by 122 publications

References 17 publications

Physiology and Pathophysiology of Proteinase-Activated Receptors (PARs): PAR-2 as a Potential Therapeutic Target

Physiology and Pathophysiology of Proteinase-Activated Receptors (PARs): PAR-2 as a Potential Therapeutic Target

TRPA1 in mast cell activation-induced long-lasting mechanical hypersensitivity of vagal afferent C-fibers in guinea pig esophagus

Prostaglandin E2Derived from Cyclooxygenases 1 and 2 Mediates Intestinal Epithelial Ion Transport Stimulated by the Activation of Protease-Activated Receptor 2

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Prostaglandin E₂Derived from Cyclooxygenases 1 and 2 Mediates Intestinal Epithelial Ion Transport Stimulated by the Activation of Protease-Activated Receptor 2