Neuropeptide K potently stimulates salivary gland secretion and potentiates substance P-induced salivation.

Takeda, Yasuo; Krause, James E.

doi:10.1073/pnas.86.1.392

Cited by 68 publications

(24 citation statements)

References 50 publications

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“…Interestingly, the PAR-2-mediated salivation and secretion of amylase or mucus from the salivary glands were resistant to pretreatment with capsaicin in vivo in the present study, although substance P, which the capsaicin-sensitive neurons abundantly contain in general, is known to be one of potent secretagogues in the salivary glands (39), thereby implying involvement of mechanisms distinct from those in the gastric mucosa. The detailed mechanisms responsible for the PAR-2-mediated salivary exocrine secretion are still largely open to question, although our recent paper has suggested involvement of tyrosine kinase (31).…”

Section: Discussioncontrasting

confidence: 53%

The protease-activated receptor-2 agonist induces gastric mucus secretion and mucosal cytoprotection

Kawabata¹,

Kinoshita²,

Nishikawa³

et al. 2001

J. Clin. Invest.

152

156

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Section: Discussioncontrasting

confidence: 53%

The protease-activated receptor-2 agonist induces gastric mucus secretion and mucosal cytoprotection

Kawabata¹,

Kinoshita²,

Nishikawa³

et al. 2001

J. Clin. Invest.

152

156

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“…The salivation bioassay was performed essentially according to the previously described method (Takeda and Krause, 1989). In brief, rats were anesthetized with i.p.…”

Section: Methodsmentioning

confidence: 99%

Protease-Activated Receptor-2 (PAR-2)-Related Peptides Induce Tear Secretion in Rats: Involvement of PAR-2 and Non-PAR-2 Mechanisms

Nishikawa

Kawai²,

Tanaka³

et al. 2004

J Pharmacol Exp Ther

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Protease-activated receptor-2 (PAR-2) plays an extensive role in the regulation of digestive exocrine secretion. The present study examined whether PAR-2-related peptides could modulate tear secretion in rats and analyzed the underlying mechanisms. SLIGRL-NH 2 , a PAR-2-activating peptide (PAR-2-AP) derived from mouse/rat PAR-2, when administered i.v. in combination with amastatin, an aminopeptidase inhibitor, evoked tear secretion, whereas LRGILS-NH 2 , a PAR-2-inactive reversed peptide, had no such effect. In contrast, LSIGRL-NH 2 , a partially reversed peptide known to be inactive with PAR-2, caused tear secretion equivalent to the effect of SLIGRL-NH 2 . SLIGKV-NH 2 , a human-derived PAR-2-AP, also induced significant tear secretion though to a lesser extent, whereas neither VKGILS-NH 2 , a reversed peptide, nor LSIGKV-NH 2 , a partially reversed peptide, produced any secretion. In desensitization experiments, after the first dose of SLIGRL-NH 2 , the second dose of SLIGRL-NH 2 produced no tear secretion, whereas the response to LSIGRL-NH 2 was only partially inhibited by preadministration of SLIGRL-NH 2 . Preadministration of LSIGRL-NH 2 abolished the response to subsequently administered LSIGRL-NH 2 but not SLIGRL-NH 2 . The tear secretion induced by LSI-GRL-NH 2 but not by PAR-2-APs was blocked by atropine or hexamethonium. Mast cell depletion due to repeated doses of compound 48/80 did not alter the effect of SLIGRL-NH 2 or LSIGRL-NH 2 . Finally, IGRL-NH 2 , a possible core structure of LSIGRL-NH 2 , triggered tear secretion in an atropine-reversible manner. Our findings suggest that the PAR-2-APs SLIGRL-NH 2 and SLIGKV-NH 2 cause tear secretion, most likely via PAR-2 and that LSIGRL-NH 2 , a PAR-2-inactive peptide, and IGRL-NH 2 , its key structure, trigger tear secretion by stimulating parasympathetic nerves via an unidentified target molecule.

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“…Salivary exocrine secretion was assessed in ddY mice and in PAR-2 Ϫ/Ϫ and PAR-2 ϩ/ϩ C57BL/6 background mice under urethane anesthesia, as described previously (Takeda and Krause, 1989;Kawabata et al, 2000b). Cotton was placed in the mouth for 1-or 5-min interval and repeatedly replaced with new cotton every 1 or 5 min.…”

Section: Potent and Metabolically Stable Par-2 Agonistsmentioning

confidence: 99%

Potent and Metabolically Stable Agonists for Protease-Activated Receptor-2: Evaluation of Activity in Multiple Assay Systems in Vitro and in Vivo

Kawabata¹,

Kanke²,

Yonezawa³

et al. 2004

J Pharmacol Exp Ther

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To develop potent and metabolically stable agonists for protease-activated receptor-2 (PAR-2), we prepared 2-furoylated (2f) derivatives of native PAR-2-activating peptides, 2f-LIGKV-OH, 2f-LIGRL-OH, 2f-LIGKV-NH 2 , and 2f-LIGRL-NH 2 , and systematically evaluated their activity in PAR-2-responsive cell lines and tissues. In both HCT-15 cells and NCTC2544 cells overexpressing PAR-2, all furoylated peptides increased cytosolic Ca 2ϩ levels with a greater potency than the corresponding native peptides, although a similar maximum response was recorded. The absolute potency of each peptide was greater in NCTC2544, possibly due to a higher level of receptor expression. Furthermore, the difference in potency between the 2-furoylated peptides and the native peptides was enhanced when evaluated in the rat superior mesenteric artery and further increased when measuring PAR-2-mediated salivation in ddY mice in vivo. The potency of 2f-LIGRL-NH 2 , the most powerful peptide, relative to SLIGKV-OH, was about 100 in the cultured cell Ca 2ϩ signaling assays, 517 in the vasorelaxation assay, and 1100 in the salivation assay. Amastatin, an aminopeptidase inhibitor, augmented salivation caused by native peptides, but not furoylated peptides. The PAR-2-activating peptides, including the furoylated derivatives, also produced salivation in the wild-type C57BL/6 mice, but not the PAR-2-deficient mice. Our data thus demonstrate that substitution of the N-terminal serine with a furoyl group in native PAR-2-activating peptides dramatically enhances the agonistic activity and decreases degradation by aminopeptidase, leading to development of 2f-LIGRL-NH 2 , the most potent peptide. Furthermore, the data from PAR-2-deficient mice provide ultimate evidence for involvement of PAR-2 in salivation and the selective nature of the 2-furoylated peptides.

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Neuropeptide K potently stimulates salivary gland secretion and potentiates substance P-induced salivation.

Cited by 68 publications

References 50 publications

The protease-activated receptor-2 agonist induces gastric mucus secretion and mucosal cytoprotection

The protease-activated receptor-2 agonist induces gastric mucus secretion and mucosal cytoprotection

Protease-Activated Receptor-2 (PAR-2)-Related Peptides Induce Tear Secretion in Rats: Involvement of PAR-2 and Non-PAR-2 Mechanisms

Potent and Metabolically Stable Agonists for Protease-Activated Receptor-2: Evaluation of Activity in Multiple Assay Systems in Vitro and in Vivo

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