title: PPARα autocrine regulation of Ca²⁺-regulated exocytosis in guinea pig antral mucous cells: NO and cGMP accumulation.
abstract: In antral mucous cells, acetylcholine (ACh, 1 μM) activates Ca(2+)-regulated exocytosis, consisting of a peak in exocytotic events that declines rapidly (initial phase) followed by a second slower decline (late phase) lasting during ACh stimulation. GW7647 [a peroxisome proliferation activation receptor α (PPARα) agonist] enhanced the ACh-stimulated initial phase, and GW6471 (a PPARα antagonist) abolished the GW7647-induced enhancement. However, GW6471 produced the delayed, but transient, increase in the ACh-stimulated late phase, and it also decreased the initial phase and produced the delayed increase in the late phase during stimulation with ACh alone. A similar delayed increase in the ACh-stimulated late phase is induced by an inhibitor of the PKG, Rp8BrPETcGMPS, suggesting that GW6471 inhibits cGMP accumulation. An inhibitor of nitric oxide synthase 1 (NOS1), N(5)-[imino(propylamino)methyl]-L-ornithine hydrochloride (N-PLA), also abolished the GW7647-induced-enhancement of ACh-stimulated initial phase but produced the delayed increase in the late phase. However, in the presence of N-PLA, an NO donor or 8BrcGMP enhanced the ACh-stimulated initial phase and abolished the delayed increase in the late phase. Moreover, GW7647 and ACh stimulated NO production and cGMP accumulation in antral mucosae, which was inhibited by GW6471 or N-PLA. Western blotting and immunohistochemistry revealed that NOS1 and PPARα colocalize in antral mucous cells. In conclusion, during ACh stimulation, a PPARα autocrine mechanism, which accumulates NO via NOS1 leading to cGMP accumulation, modulates the Ca(2+)-regulated exocytosis in antral mucous cells.
authors.affiliation: Nakahari Project of Central Research Laboratory, Laboratory of Pharmacotherapy, Osaka University of Pharmaceutical Sciences, Takatsuki, Japan.
authors.forename: Saori
authors.initials: S
authors.lastname: Tanaka
authors.affiliation: Nakahari Project of Central Research Laboratory, Laboratory of Pharmacotherapy, Osaka University of Pharmaceutical Sciences, Takatsuki, Japan.
authors.forename: Nanae
authors.initials: N
authors.lastname: Sugiyama
authors.affiliation: Nakahari Project of Central Research Laboratory, Mechanobiology Laboratory, Graduate School of Medicine, Nagoya University, Nagoya, Japan, and.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Takahashi
authors.affiliation: Nakahari Project of Central Research Laboratory, Laboratory of Pharmacotherapy, Osaka University of Pharmaceutical Sciences, Takatsuki, Japan.
authors.forename: Daiki
authors.initials: D
authors.lastname: Mantoku
authors.affiliation: Nakahari Project of Central Research Laboratory, Department of Molecular Cell Physiology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Yukinori
authors.initials: Y
authors.lastname: Sawabe
authors.affiliation: Nakahari Project of Central Research Laboratory, Department of Pathology, and.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Kuwabara
authors.affiliation: Nakahari Project of Central Research Laboratory, Department of Microbiology and Infection Control, Osaka Medical College, Takatsuki, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Nakano
authors.affiliation: Laboratory of Pharmacotherapy, Osaka University of Pharmaceutical Sciences, Takatsuki, Japan.
authors.forename: Chikao
authors.initials: C
authors.lastname: Shimamoto
authors.affiliation: Laboratory of Pharmacotherapy, Osaka University of Pharmaceutical Sciences, Takatsuki, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Matsumura
authors.affiliation: Nakahari Project of Central Research Laboratory, Department of Molecular Cell Physiology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Marunaka
authors.affiliation: Nakahari Project of Central Research Laboratory, Department of Molecular Cell Physiology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan nakahari@koto.kpu-m.ac.jp.
authors.forename: Takashi
authors.initials: T
authors.lastname: Nakahari
mesh_terms: D000818:Animals; D019898:Autocrine Communication / Q000187:drug effects / Q000502:physiology*; D002087:Butyrates / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D005089:Exocytosis / Q000187:drug effects / Q000502:physiology*; D005753:Gastric Mucosa / Q000187:drug effects / Q000378:metabolism; D020397:Goblet Cells / Q000187:drug effects / Q000378:metabolism*; D006168:Guinea Pigs; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D010080:Oxazoles / Q000494:pharmacology; D047493:PPAR alpha / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010671:Phenylurea Compounds / Q000494:pharmacology; D011706:Pyloric Antrum / Q000187:drug effects / Q000378:metabolism*; D014443:Tyrosine / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D002087:Butyrates; C449302:GW 6471; C453899:GW 7647; D010080:Oxazoles; D047493:PPAR alpha; D010671:Phenylurea Compounds; D009569:Nitric Oxide; D014443:Tyrosine; D006152:Cyclic GMP; D002118:Calcium
keywords: NOS1; acetylcholine; arachidonic acid; gastric mucin secretion