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

摘要

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 LSI<3RL-NH_2 was only partially inhibited by pread-ministration 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.