title: Human group IIA secretory phospholipase A2 potentiates Ca2+ influx through L-type voltage-sensitive Ca2+ channels in cultured rat cortical neurons.
abstract: Mammalian group IIA secretory phospholipase A2 (sPLA2-IIA) generates prostaglandin D2 (PGD2) and triggers apoptosis in cortical neurons. However, mechanisms of PGD2 generation and apoptosis have not yet been established. Therefore, we examined how second messengers are involved in the sPLA2-IIA-induced neuronal apoptosis in primary cultures of rat cortical neurons. sPLA2-IIA potentiated a marked influx of Ca2+ into neurons before apoptosis. A calcium chelator and a blocker of the L-type voltage-sensitive Ca2+ channel (L-VSCC) prevented neurons from sPLA2-IIA-induced neuronal cell death in a concentration-dependent manner. Furthermore, the L-VSCC blocker ameliorated sPLA2-IIA-induced morphologic alterations and apoptotic features such as condensed chromatin and fragmented DNA. Other blockers of VSCCs such as N type and P/Q types did not affect the neurotoxicity of sPLA2-IIA. Blockers of L-VSCC significantly suppressed sPLA2-IIA-enhanced Ca2+ influx into neurons. Moreover, reactive oxygen species (ROS) were generated prior to apoptosis. Radical scavengers reduced not only ROS generation, but also the sPLA2-IIA-induced Ca2+ influx and apoptosis. In conclusion, we demonstrated that sPLA2-IIA potentiates the influx of Ca2+ into neurons via L-VSCC. Furthermore, the present study suggested that eicosanoids and ROS generated during arachidonic acid oxidative metabolism are involved in sPLA2-IIA-induced apoptosis in cooperation with Ca2+.
authors.affiliation: Discovery Research Laboratories, Shionogi and Co. Ltd, Osaka, Japan. tatsurou.yagami@shionogi.co.jp
authors.forename: Tatsurou
authors.initials: T
authors.lastname: Yagami
authors.forename: Keiichi
authors.initials: K
authors.lastname: Ueda
authors.forename: Kenji
authors.initials: K
authors.lastname: Asakura
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Nakazato
authors.forename: Satoshi
authors.initials: S
authors.lastname: Hata
authors.forename: Takayuki
authors.initials: T
authors.lastname: Kuroda
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Sakaeda
authors.forename: Gaku
authors.initials: G
authors.lastname: Sakaguchi
authors.forename: Naohiro
authors.initials: N
authors.lastname: Itoh
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Hashimoto
authors.forename: Yozo
authors.initials: Y
authors.lastname: Hori
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D016718:Arachidonic Acid / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D002614:Chelating Agents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015777:Eicosanoids / Q000096:biosynthesis; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000494:pharmacology; D054501:Group II Phospholipases A2; D006801:Humans; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D010741:Phospholipases A / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D054467:Phospholipases A2; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors / Q000378:metabolism; D015290:Second Messenger Systems / Q000187:drug effects / Q000502:physiology
chemical_list: D002121:Calcium Channel Blockers; D015220:Calcium Channels; D020746:Calcium Channels, L-Type; D002614:Chelating Agents; D015777:Eicosanoids; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D016166:Free Radical Scavengers; D017382:Reactive Oxygen Species; D016718:Arachidonic Acid; D010741:Phospholipases A; D054501:Group II Phospholipases A2; D054467:Phospholipases A2; D002118:Calcium