Peroxisome proliferation activation receptor alpha modulation of Ca super(2+)-regulated exocytosis via arachidonic acid in guinea-pig antral mucous cells

• Published in: Experimental physiology Vol. 95; no. 8; pp. 858 - 868
• Main Authors: Sawabe, Yukinori, Shimamoto, Chikao, Sakai, Akiko, Kuwabara, Hiroko, Saad, Adel H, Nakano, Takashi, Takitani, Kimitaka, Tamai, Hiroshi, Mori, Hiroshi, Marunaka, Yoshinori, Nakahari, Takashi
• Format: Journal Article
• Language: English
• Published: 01.08.2010
• DOI: 10.1113/expphysiol.2010.053603
• ISSN: 0958-0670

Indomethacin (IDM, 10 mu m), not aspirin (ASA; 10 mu m), enhanced the Ca super(2+)-regulated exocytosis stimulated by 1 mu m acetylcholine (ACh) in guinea-pig antral mucous cells. Indomethacin inhibits prostaglandin G/H (PGG/H) and 15R-hydroperoxy-eicosatetraenoic acid (15R-HPETE) production from arachidonic acid (AA), while ASA inhibits PGG/H production but accelerates 15R-HPETE production. This suggests that IDM accumulates AA. Arachidonic acid (2 mu m) enhanced Ca super(2+)-regulated exocytosis in antral mucous cells to a similar extent to IDM. Moreover, a stable analogue of AA, arachidonyltrifluoromethyl ketone (AACOCF sub(3)), also enhanced Ca super(2+)-regulated exocytosis, indicating that AA, not products from AA, enhances Ca super(2+)-regulated exocytosis. We hypothesized that AA activates peroxisome proliferation activation receptor alpha (PPAR alpha ), because AA is a natural ligand for PPAR alpha . A PPAR alpha agonist (WY14643; 1 mu m) enhanced Ca super(2+)-regulated exocytosis, and a PPAR alpha blocker (MK886; 50 mu m) abolished the enhancement of Ca super(2+)-regulated exocytosis induced by AA, IDM, AACOCF sub(3) and WY14643. Western blotting and immunohistochemical examinations demonstrated that PPAR alpha exists in antral mucous cells. Moreover, MK886 decreased the frequency of Ca super(2+)-regulated exocytosis activated by 1 mu m ACh or 2 mu m thapsigargin alone by 25-30%. Thus, ACh stimulates AA accumulation via an [Ca super(2+)] sub(i) increase, which activates PPAR alpha , leading to enhancement of Ca super(2+)-regulated exocytosis in antral mucous cells. A novel autocrine mechanism mediated via PPAR alpha enhances Ca super(2+)-regulated exocytosis in guinea-pig antral mucous cells.