title: Caffeine-inducible ATP release is mediated by Ca2+-signal transducing system from the endoplasmic reticulum to mitochondria.
abstract: Adenosine triphosphate (ATP) is released as an autocrine/paracrine signal from a variety of cells. The present study was undertaken to clarify the Ca2+-signal pathway involved in the caffeine-inducible release of ATP from cultured smooth muscle cells (SMC). The release of ATP induced by caffeine (3 mM) was almost completely inhibited by ryanodine and tetracaine, but not by 2-APB, thus being mediated by ryanodine receptors (RyR). The expression of messenger RNA from only RyR-2 was detected in the cells. Furthermore, the induced release was attenuated by mitochondrial inhibitors, rotenone and oligomycin and by Cl- channel blockers, niflumic acid, and 5-nitro-2-(3-phenylpropylamino)-benzoic acid. Increase in Ca2+-signals with fluo 4 and rhod-2 caused by caffeine were reduced by tetracaine and oligomycin plus carbonyl cyanide m-chlorophenylhydrazone, respectively. A close spatial relation between the endoplasmic reticulum (ER) and mitochondria was electromicroscopically observed in the SMC, supporting the existence of a Ca2+-signaling bridge on both the organelli. These results suggest that caffeine stimulates ryanodine receptor (RyR-2) and facilitates a Ca2+-signal transducing system from ER to mitochondria, and then, the signal appears to accelerate the ATP synthesis in mitochondria. In addition, the mitochondrial event may lead further cell signaling to the cell membrane and activates Cl- channels, resulting in the extracellular release of cytosolic ATP.
authors.affiliation: Department of Pharmacology, Fukuoka University, Fukuoka, 814-0180, Japan. katsurag@fukuoka-u.ac.jp
authors.forename: Takeshi
authors.initials: T
authors.lastname: Katsuragi
authors.forename: Chiemi
authors.initials: C
authors.lastname: Sato
authors.forename: Sadaharu
authors.initials: S
authors.lastname: Usune
authors.forename: Shinya
authors.initials: S
authors.lastname: Ueno
authors.forename: Masaru
authors.initials: M
authors.lastname: Segawa
authors.forename: Keisuke
authors.initials: K
authors.lastname: Migita
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D002110:Caffeine / Q000494:pharmacology*; D020013:Calcium Signaling / Q000187:drug effects*; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D006168:Guinea Pigs; D008297:Male; D008931:Mitochondria, Muscle / Q000187:drug effects / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel / Q000187:drug effects* / Q000378:metabolism; D014649:Vas Deferens / Q000166:cytology / Q000187:drug effects
chemical_list: D012333:RNA, Messenger; D019837:Ryanodine Receptor Calcium Release Channel; D002110:Caffeine; D000255:Adenosine Triphosphate