Protease-activated receptor-2 (PAR-2) in the pancreas and parotid gland: Immunolocalization and involvement of nitric oxide in the evoked amylase secretion

Kawabata, Atsufumi; Kuroda, R.; Nishida, Motohiro; Nagata, Nanae; Sakaguchi, Yuriko; Kawao, Naoyuki; Nishikawa, Hiroyuki; Arizono, Naoki; Kawai, Kenzo

doi:10.1016/s0024-3205(02)02044-1

Cited by 65 publications

(56 citation statements)

References 38 publications

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“…Within the oral cavity, administration of PAR 2 -AP but not PAR 1 -AP into the parotid duct increased Fos expression in nociceptive neurons located in laminas I and II of the caudal part of the spinal trigeminal nucleus, which corresponds functionally to the spinal cord dorsal horn [18]. Thus, PAR 2 seems to be involved in the development of parotid pain [18].…”

Section: Protease-activated Receptors and Hypersensitivity Of The Gasmentioning

confidence: 94%

“…Thus, PAR 2 seems to be involved in the development of parotid pain [18]. Co-administration of PAR 1 and PAR 2 -AP into the parotid duct did not suppress the increase in Fos expression due to PAR 2 activation, suggesting that PAR 1 could not be antinociceptive in parotid pain [18]. Similarly, intracolonic injections of PAR 2 -AP increase Fos expression in neurons from laminae I and II of the spinal cord (segment L4-L6) in rat [19].…”

Section: Protease-activated Receptors and Hypersensitivity Of The Gasmentioning

confidence: 98%

Section: Protease-activated Receptors and Hypersensitivity Of The Gasmentioning

confidence: 98%

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Protease-Activated Receptors as Therapeutic Targets in Visceral Pain

Cenac

2013

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Abstract:The protease-activated receptors (PARs) play a pivotal role in inflammatory and nociceptive processes. PARs have raised considerable interest because of their capacity to regulate numerous aspects of viscera physiology and pathophysiology. The present article summarizes research on PARs and proteases as signalling molecules in visceral pain. In particular, experiments in animal models suggest that PAR 2 is important for visceral hypersensitivity. Moreover, endogenous PAR 2 agonists seem to be released by colonic tissue of patients suffering from irritable bowel syndrome, suggesting a role for this receptor in visceral pain perception. Thus, PARs, together with proteases that activate them, represent exciting targets for therapeutic intervention on visceral pain.

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Section: Protease-activated Receptors and Hypersensitivity Of The Gasmentioning

confidence: 94%

Section: Protease-activated Receptors and Hypersensitivity Of The Gasmentioning

confidence: 98%

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Protease-Activated Receptors as Therapeutic Targets in Visceral Pain

Cenac

2013

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“…It is widely expressed, including in the pancreas (9,10,17), and can be activated by either trypsin or mast cell tryptase (30). In the present communication, we have employed a novel pepducin PAR2 antagonist (27) to pharmacologically inhibit PAR2, and we have evaluated the effect of pharmacological PAR2 inhibition on pancreatitis severity.…”

mentioning

confidence: 99%

Pharmacological inhibition of PAR2 with the pepducin P2pal-18S protects mice against acute experimental biliary pancreatitis

Michael

Kuliopulos

Covic

et al. 2013

American Journal of Physiology-Gastrointestinal and Liver Physi

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Michael ES, Kuliopulos A, Covic L, Steer ML, Perides G. Pharmacological inhibition of PAR2 with the pepducin P2pal-18S protects mice against acute experimental biliary pancreatitis. Am J Physiol Gastrointest Liver Physiol 304: G516 -G526, 2013. First published December 28, 2012 doi:10.1152/ajpgi.00296.2012.-Pancreatic acinar cells express proteinase-activated receptor-2 (PAR2) that is activated by trypsin-like serine proteases and has been shown to exert model-specific effects on the severity of experimental pancreatitis, i.e., PAR2 Ϫ/Ϫ mice are protected from experimental acute biliary pancreatitis but develop more severe secretagogue-induced pancreatitis. P2pal-18S is a novel pepducin lipopeptide that targets and inhibits PAR2. In studies monitoring PAR2-stimulated intracellular Ca 2ϩ concentration changes, we show that P2pal-18S is a full PAR2 inhibitor in acinar cells. Our in vivo studies show that P2pal-18S significantly reduces the severity of experimental biliary pancreatitis induced by retrograde intraductal bile acid infusion, which mimics injury induced by endoscopic retrograde cholangiopancreatography (ERCP). This reduction in pancreatitis severity is observed when the pepducin is given before or 2 h after bile acid infusion but not when it is given 5 h after bile acid infusion. Conversely, P2pal-18S increases the severity of secretagogue-induced pancreatitis. In vitro studies indicate that P2pal-18S protects acinar cells against bile acid-induced injury/death, but it does not alter bile acid-induced intracellular zymogen activation. These studies are the first to report the effects of an effective PAR2 pharmacological inhibitor on pancreatic acinar cells and on the severity of experimental pancreatitis. They raise the possibility that a pepducin such as P2pal-18S might prove useful in the clinical management of patients at risk for developing severe biliary pancreatitis such as occurs following ERCP.proteinase-activated receptors; calcium; bile acid receptors; Gpbar1; proteinase-activated receptor-2 ACUTE PANCREATITIS IS AN INFLAMMATORY process most commonly associated with either biliary tract stone disease, abuse of ethanol, or performance of the endoscopic retrograde cholangiopancreatography (ERCP) procedure. The morbidity and mortality rates of acute pancreatitis are directly related to its severity, but, to date, no specific therapy for clinical acute pancreatitis has been identified. In general, the diagnosis of acute pancreatitis is only made after the disease is well established, and, as a result, clinical studies exploring the early cellular events and mechanisms that regulate the severity of an acute pancreatitis attack have not been possible. As an alternative, most investigators probing these processes have, by necessity, utilized experimental models of pancreatitis in laboratory animals for their studies.The most frequently used of those models involves either administration of a supramaximally stimulating dose of a secretagogue (i.e., the cholecystokinin analog caerulein) or retrograde ...

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“…Serine proteases, including trypsin and tryptase, are endogenous activators of PAR-2, and the cleavage mediated by these proteases generated a distinct N-terminal tethered ligand sequence (SLIGRL and SLIGKV for murine and human PAR-2, respectively) (Nystedt et al, 1994;Kawabata and Kuroda, 2000;Macfarlane et al, 2001). Synthetic peptides based on the receptor-activating sequence of the tethered ligand (SLIGRL and SLIGKV) are also capable of activating PAR-2 by direct binding to the receptor (Kawabata et al, 2000a(Kawabata et al, ,b, 2001(Kawabata et al, , 2002bOshiro et al, 2002). Since its cloning, the expression and functional role of PAR-2 have been elucidated in various tissues (Kawabata et al, 2000a(Kawabata et al, , 2001(Kawabata et al, , 2002bMacfarlane et al, 2001).…”

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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

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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.

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Protease-activated receptor-2 (PAR-2) in the pancreas and parotid gland: Immunolocalization and involvement of nitric oxide in the evoked amylase secretion

Cited by 65 publications

References 38 publications

Protease-Activated Receptors as Therapeutic Targets in Visceral Pain

Protease-Activated Receptors as Therapeutic Targets in Visceral Pain

Pharmacological inhibition of PAR2 with the pepducin P2pal-18S protects mice against acute experimental biliary pancreatitis

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

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