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First published on August 26, 2004; DOI: 10.1124/jpet.104.072074

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Received for publication June 1, 2004.
Revised August 24, 2004.
Accepted for publication August 26, 2004.

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

Hiroyuki Nishikawa 1, Kenzo Kawai 1, Makoto Tanaka 1, Hiroya Ohtani 1, Shuichi Tanaka 1, Chizuko Kitagawa 1, Minoru Nishida 1, Tomoyuki Abe 1, Hiromasa Araki 1, Atsufumi Kawabata 2*

1 Fuso Pharmaceutical Industries Ltd. 2 School of Pharmaceutical Sciences, Kinki University

* Address correspondence to: E-mail: kawabata{at}phar.kindai.ac.jp

Abstract

Protease-activated receptor-2 (PAR-2) plays extensive roles in regulation of digestive exocrine secretion. The present study examined if PAR-2-related peptides could modulate tear secretion in rats and analyzed the underlying mechanisms. SLIGRL-NH2, 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, while LRGILS-NH2, a PAR-2-inactive reversed peptide, had no such effect. In contrast, LSIGRL-NH2, a partially reversed peptide known to be inactive on PAR-2, caused tear secretion, an effect being equivalent to the effect of SLIGRL-NH2. SLIGKV-NH2, a human-derived PAR-2-AP, also induced significant tear secretion, though to a lesser extent, whereas neither VKGILS-NH2, a reversed peptide, nor LSIGKV-NH2, a partially reversed peptide, produced no secretion. In desensitization experiments, after a dose of SLIGRL-NH2, the second dose of SLIGRL-NH2 produced no tear secretion, while the response to LSIGRL-NH2 was only partially inhibited by pre-administration of SLIGRL-NH2. Pre-administration of LSIGRL-NH2 abolished the response to subsequently administered LSIGRL-NH2, but not SLIGRL-NH2. The tear secretion induced by LSIGRL-NH2, but not PAR-2-APs, was blocked by atropine or hexamethonium. Mast cell depletion by repeated doses of compound 48/80 unaffected the effect of SLIGRL-NH2 or LSIGRL-NH2. Finally, IGRL-NH2 a possible core structure of LSIGRL-NH2, triggered tear secretion in an atropine-reversible manner. Our findings suggest that SLIGRL-NH2 and SLIGKV-NH2, PAR-2-APs, cause tear secretion most probably via PAR-2, and that LSIGRL-NH2, a PAR-2-inactive peptide, and also IGRL-NH2, its key structure, trigger tear secretion by stimulating parasympathetic nerves via an unidentified target molecule.


Key words: PAR-2, exocrine secretion, parasympathetic nerve, peptide, protease-activated receptor, tear




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