Signal Transduction Pathways Involved in the Mechanical Responses to Protease-Activated Receptors in Rat Colon

Mulè, Flavia; Baffi, Maria Carmela; Falzone, Mariarita; Cerra, Maria Carmela

doi:10.1124/jpet.102.041301

Cited by 33 publications

(31 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These differences can be explained, in part, by reports that vascular smooth muscle relaxation is attributed to PAR-2 on endothelium (14), whereas vascular contraction is mediated by PAR-1 located on smooth muscle (24). The concentration-dependent contraction, however, is consistent with studies in rats in which the contraction was mediated by activation of phospholipase C (23).…”

Section: Discussioncontrasting

confidence: 41%

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

Zhao

Shea‐Donohue

2003

American Journal of Physiology-Gastrointestinal and Liver Physi

View full text Add to dashboard Cite

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

show abstract

Section: Discussioncontrasting

confidence: 41%

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

Zhao

Shea‐Donohue

2003

American Journal of Physiology-Gastrointestinal and Liver Physi

View full text Add to dashboard Cite

show abstract

“…Intestinal motility also seems to be affected by PAR 1 activation. Administration of a PAR 1 -activating peptide causes a reduction of the spontaneous contractions in intestinal circular muscle preparations and a contractile effect or a biphasic relaxation followed by contraction in a longitudinal muscle preparation of rat intestine (20,21).…”

Section: Introductionmentioning

confidence: 99%

A role for proteinase-activated receptor–1 in inflammatory bowel diseases

et al. 2004

View full text Add to dashboard Cite

Proteinase-activated receptor-1 (PAR 1 ), a G protein-coupled receptor activated by thrombin, is highly expressed in different cell types of the gastrointestinal tract. The activity of thrombin and of other proteinases is significantly increased in the colon of inflammatory bowel disease (IBD) patients. Since PAR 1 activation in tissues other than the gut provoked inflammation, we hypothesized that PAR 1 activation in the colon is involved in the pathogenesis of IBD. Here, we demonstrate that PAR 1 is overexpressed in the colon of IBD patients. In mice, intracolonic administration of PAR 1 agonists led to an inflammatory reaction characterized by edema and granulocyte infiltration. This PAR 1 activation-induced inflammation was dependent on B and T lymphocytes. Moreover, PAR 1 activation exacerbated and prolonged inflammation in a mouse model of IBD induced by the intracolonic administration of trinitrobenzene sulfonic acid (TNBS), while PAR 1 antagonism significantly decreased the mortality and severity of colonic inflammation induced by TNBS and dextran sodium sulfate. In these 2 models, colitis development was strongly attenuated by PAR 1 deficiency. Taken together, these results imply an important role for PAR 1 in the pathogenesis of experimental colitis, supporting the notion that PAR 1 inhibition may be beneficial in the context of IBD and possibly in other chronic intestinal inflammatory disorders.

show abstract

“…PAR-2 activation induces [Ca 2ϩ ] i increase in guinea pig tracheal epithelial cells (Oshiro et al, 2002), rat longitudinal muscle cells (Mule et al, 2002), and some cell lines (Kawabata et al, 2004a) or activates phospholipase C in longitudinal muscle (Mule et al, 2002 (Nakamura et al, 2004), activation of mAChRs also induced [Ca 2ϩ ] i increases in the SMG cells. Taken together with the composition of saliva, PAR-2 mediates salivary secretion by a Ca 2ϩ -dependent mechanism that is similar to mAChRs-mediated salivary secretion.…”

Section: Discussionmentioning

confidence: 99%

Up-Regulated PAR-2-Mediated Salivary Secretion in Mice Deficient in Muscarinic Acetylcholine Receptor Subtypes

Nishiyama¹,

Nakamura²,

Obara³

et al. 2006

J Pharmacol Exp Ther

View full text Add to dashboard Cite

Protease-activated receptor-2 (PAR-2) is expressed in the salivary glands and is expected to be a new target for the treatment of exocrine dysfunctions, such as dry mouth; however, the salivary secretory mechanism mediated by PAR-2 remains to be elucidated. Therefore, mechanism of the PAR-2-mediated salivary secretion was investigated in this study. We found that a PAR-2 agonist peptide, SLIGRL-OH, induced salivary flow in vivo and dose-dependent increase in [Ca 2ϩ ] i submandibular gland (SMG) acinar cells in wild-type (WT) mice and mice lacking M 3 or both M 1 and M 3 muscarinic acetylcholine receptors (mAChRs), whereas secretions in PAR-2 knockout (PAR-2KO) mice were completely abolished. The saliva composition secreted by SLIGRL-OH was similar to that secreted by mAChR stimulation. Ca 2ϩ imaging in WT acinar cells and ␤-galactosidase staining in PAR-2KO mice, in which the ␤-galactosidase gene (LacZ) was incorporated into the disrupted gene, revealed a nonubiquitous, sporadic distribution of PAR-2 in the SMG. Furthermore, compared with the secretion in WT mice, PAR-2-mediated salivary secretion and Ca 2ϩ response were enhanced in mice lacking M 3 or both M 1 and M 3 mAChRs, in which mAChR-stimulated secretion and Ca 2ϩ response in acinar cells were severely impaired. Although the mechanism underlying the enhanced PAR-2-mediated salivary secretion in M 3 -deficient mice is not clear, the result suggests the presence of some compensatory mechanism involving PAR-2 in the salivary glands deficient in cholinergic activation. These results indicate that PAR-2 present in the salivary glands mediates Ca 2ϩ -dependent fluid secretion, demonstrating potential usefulness of PAR-2 as a target for dry mouth treatment.

show abstract

Signal Transduction Pathways Involved in the Mechanical Responses to Protease-Activated Receptors in Rat Colon

Cited by 33 publications

References 35 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

A role for proteinase-activated receptor–1 in inflammatory bowel diseases

Up-Regulated PAR-2-Mediated Salivary Secretion in Mice Deficient in Muscarinic Acetylcholine Receptor Subtypes

Contact Info

Product

Resources

About