Protease-activated receptor-2 (PAR-2)-related peptides induce tear secretion in rats: involvement of PAR-2 and non-PAR-2 mechanisms.
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 LSIGRL-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.
Nishikawa
Hiroyuki
H
Research and Development Center, Fuso Pharmaceutical Industries Ltd., Osaka, Japan.
Kawai
Kenzo
K
Tanaka
Makoto
M
Ohtani
Hiroya
H
Tanaka
Shuichi
S
Kitagawa
Chizuko
C
Nishida
Minoru
M
Abe
Tomoyuki
T
Araki
Hiromasa
H
Kawabata
Atusufumi
A
D000758:Anesthesia; D000818:Animals; D051379:Mice; D009842:Oligopeptides / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D044464:Receptor, PAR-2 / Q000502:physiology*; D013666:Tears / Q000187:drug effects / Q000378:metabolism*; D014851:Wakefulness
D009842:Oligopeptides; D010455:Peptides; D044464:Receptor, PAR-2; C112356:seryl-leucyl-isoleucyl-glycyl--arginyl-leucinamide