Agonists of proteinase-activated receptor 2 excite guinea pig ileal myenteric neurons

Linden, David R.; Manning, Brian P.; Bunnett, Nigel W.; Mawe, Gary M.

doi:10.1016/s0014-2999(01)01447-9

Cited by 44 publications

(31 citation statements)

References 11 publications

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“…The contraction was inhibited by TTX but not by atropine, implying a role for noncholinergic excitatory nerves. Others have reported (19) that activation of PARs on myenteric neurons in the guinea pig ileum elicits a prolonged depolarization and excitation. Immunoreactive PAR-1 and PAR-2 could be detected in approximately two-thirds of the neurons from the myenteric plexus of guinea pig small intestine in primary culture, and RT-PCR further confirmed the expression of PAR-1 and PAR-2 in the myenteric plexus (11).…”

Section: Discussionmentioning

confidence: 98%

PAR-2 agonists induce contraction of murine small intestine through neurokinin receptors

Zhao

Shea‐Donohue

2003

American Journal of Physiology-Gastrointestinal and Liver Physi

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Zhao, Aiping, and Terez Shea-Donohue. PAR-2 agonists induce contraction of murine small intestine through neurokinin receptors. Am J Physiol Gastrointest Liver Physiol 285: G696-G703, 2003. First published June 11, 2003 10.1152/ajpgi.00064.2003.-Protease-activated receptor-2 (PAR-2) is a G protein-coupled receptor and is expressed throughout the gut. It is well known that PAR-2 participates in the regulation of gastrointestinal motility; however, the results are inconsistent. The present study investigated the effect and mechanism of PAR-2 activation on murine small intestinal smooth muscle function in vitro. Both trypsin and PAR-2-activating peptide SLIGRL induced a small relaxation followed by a concentration-dependent contraction. The sensitivity to trypsin was greater than that to SLIGRL (EC50 ϭ 0.03 vs. 40 M), but maximal responses were similar (12.3 Ϯ 1.6 vs. 13.7 Ϯ 1.3 N/cm 2 ). Trypsinevoked contraction (1 M) exhibited a rapid desensitization, whereas the desensitization of response to SLIGRL was less even at high concentration (50 M). Atropine had no effect on PAR-2 agonist-induced contractions. In contrast, TTX and capsaicin significantly attenuated those contractions, implicating a neurogenic mechanism that may involve capsaicinsensitive sensory nerves. Furthermore, contractions induced by trypsin and SLIGRL were reduced by neurokinin receptor NK1 antagonist SR-140333 or NK2 antagonist SR-48968 alone or were further reduced by combined application of SR-140333 and SR-48968, indicating the involvement of neurokinin receptors. In addition, desensitizing neurokinin receptors with substance P and/or neurokinin A decreased the PAR-2 agonist-evoked contraction. We concluded that PAR-2 agonists induced a contraction of murine intestinal smooth muscle that was mediated by nerves. The excitatory effect is also dependent on sensory neural pathways and requires both NK1 and NK2 receptors. mouse; protease-activated receptor; trypsin PROTEASE-ACTIVATED RECEPTORS (PARs) are a novel subclass of the seven-transmembrane-spanning, G protein-coupled receptors. Rather than being stimulated through ligand receptor occupancy, PARs are activated by a unique mechanism that involves recognition of the receptor by a protease, cleavage of the receptor at a specific enzymatic site located at the extracellular NH 2

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Section: Discussionmentioning

confidence: 98%

PAR-2 agonists induce contraction of murine small intestine through neurokinin receptors

Zhao

Shea‐Donohue

2003

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…We did not expect to find a common pattern of responses in these tissues that would suggest common mediators (proteases and PAR 2 ) in all IBS patients, despite the variability in clinical presentation. Whether PAR 2 and proteases contribute to altered bowel frequency and stool consistency is not known, but the fact that PAR 2 activation leads to changes in intrinsic and extrinsic primary afferents (33,34,45,58) is not inconsistent with these findings, since alterations in sensory processing in the gut wall could just as easily lead to enhanced as reduced motility, for example. Since similar findings for PAR 2 and proteolytic activity were observed regardless of the IBS subtype, we cannot exclude the possibility that PAR 2 activation and protease release could be a feature common to all colonic pathologies associated with hyperalgesia.…”

Section: Figurementioning

confidence: 99%

Role for protease activity in visceral pain in irritable bowel syndrome

Cenac¹,

Andrews²,

Holzhausen³

et al. 2007

J. Clin. Invest.

515

551

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Mediators involved in the generation of symptoms in patients with irritable bowel syndrome (IBS) are poorly understood. Here we show that colonic biopsy samples from IBS patients release increased levels of proteolytic activity (arginine cleavage) compared to asymptomatic controls. This was dependent on the activation of NF-κB. In addition, increased proteolytic activity was measured in vivo, in colonic washes from IBS compared with control patients. Trypsin and tryptase expression and release were increased in colonic biopsies from IBS patients compared with control subjects. Biopsies from IBS patients (but not controls) released mediators that sensitized murine sensory neurons in culture. Sensitization was prevented by a serine protease inhibitor and was absent in neurons lacking functional protease-activated receptor-2 (PAR 2 ). Supernatants from colonic biopsies of IBS patients, but not controls, also caused somatic and visceral hyperalgesia and allodynia in mice, when administered into the colon. These pronociceptive effects were inhibited by serine protease inhibitors and a PAR 2 antagonist and were absent in PAR 2 -deficient mice. Our study establishes that proteases are released in IBS and that they can directly stimulate sensory neurons and generate hypersensitivity symptoms through the activation of PAR 2 .

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“…Activation of PAR 2 on enteric neurons results in depolarization and sustained hyperexcitability (Linden et al, 2001;Gao et al, 2002;Reed et al, 2003). We therefore determined whether PAR 2 activation depolarized small-and medium-diameter DRG neurons in culture and lowered their firing threshold, thereby increasing their excitability to other stimuli, by measuring the rheobase (minimum current to evoke one action potential in the current-clamp mode).…”

Section: Par 2 Agonists Increased Excitability Of Drg Neuronsmentioning

confidence: 99%

Protease-Activated Receptor 2 Sensitizes the Capsaicin Receptor Transient Receptor Potential Vanilloid Receptor 1 to Induce Hyperalgesia

Amadesi¹,

Nie

Vergnolle³

et al. 2004

J. Neurosci.

378

369

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Agonists of proteinase-activated receptor 2 excite guinea pig ileal myenteric neurons

Cited by 44 publications

References 11 publications

PAR-2 agonists induce contraction of murine small intestine through neurokinin receptors

PAR-2 agonists induce contraction of murine small intestine through neurokinin receptors

Role for protease activity in visceral pain in irritable bowel syndrome

Protease-Activated Receptor 2 Sensitizes the Capsaicin Receptor Transient Receptor Potential Vanilloid Receptor 1 to Induce Hyperalgesia

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