title: Nitric Oxide-induced Activation of the Type 1 Ryanodine Receptor Is Critical for Epileptic Seizure-induced Neuronal Cell Death.
abstract: Status epilepticus (SE) is a life-threatening emergency that can cause neurodegeneration with debilitating neurological disorders. However, the mechanism by which convulsive SE results in neurodegeneration is not fully understood. It has been shown that epileptic seizures produce markedly increased levels of nitric oxide (NO) in the brain, and that NO induces Ca2+release from the endoplasmic reticulum via the type 1 ryanodine receptor (RyR1), which occurs through S-nitrosylation of the intracellular Ca2+release channel. Here, we show that through genetic silencing of NO-induced activation of the RyR1 intracellular Ca2+release channel, neurons were rescued from seizure-dependent cell death. Furthermore, dantrolene, an inhibitor of RyR1, was protective against neurodegeneration caused by SE. These results demonstrate that NO-induced Ca2+release via RyR is involved in SE-induced neurodegeneration, and provide a rationale for the use of RyR1 inhibitors for the prevention of brain damage following SE.
authors.affiliation: Department of Pharmacology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan; Department of Physiology, School of Medicine, Faculty of Medicine, Toho University, 5-21-16 Omori-Nishi, Ota-ku, Tokyo 143-8540, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Mikami
authors.affiliation: Department of Pharmacology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Kanemaru
authors.affiliation: Department of Pharmacology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Yohei
authors.initials: Y
authors.lastname: Okubo
authors.affiliation: Department of Pharmacology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Nakaune
authors.affiliation: Department of Pharmacology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Junji
authors.initials: J
authors.lastname: Suzuki
authors.affiliation: Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Shibata
authors.affiliation: Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Sugiyama
authors.affiliation: Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Ryuta
authors.initials: R
authors.lastname: Koyama
authors.affiliation: Department of Pharmacology, Graduate School of Medicine, Juntendo University, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Murayama
authors.affiliation: Department of Neurosurgery, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan; Department of Neurosurgery, Graduate School of Medicine, Teikyo University, 2-11-1 Kaga, Itabashi-Ku, Tokyo 117-003, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Ito
authors.affiliation: Department of Molecular Physiology, The Jikei University School of Medicine, 3-25-8 Nishishimbashi, Minato-ku, Tokyo 105-8461, Japan.
authors.forename: Toshiko
authors.initials: T
authors.lastname: Yamazawa
authors.affiliation: Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Ikegaya
authors.affiliation: Department of Pharmacology, Graduate School of Medicine, Juntendo University, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Sakurai
authors.affiliation: Department of Neurosurgery, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Nobuhito
authors.initials: N
authors.lastname: Saito
authors.affiliation: Department of Biological Chemistry, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan. Electronic address: kakizawa.sho.4u@kyoto-u.ac.jp.
authors.forename: Sho
authors.initials: S
authors.lastname: Kakizawa
authors.affiliation: Department of Pharmacology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan; Department of Cellular and Molecular Pharmacology, Nihon University School of Medicine, 30-1 Oyaguchi Kami-cho, Itabashi-ku, Tokyo 173-8610, Japan. Electronic address: iino@m.u-tokyo.ac.jp.
authors.forename: Masamitsu
authors.initials: M
authors.lastname: Iino
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002120:Calcium Channel Agonists / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004827:Epilepsy / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007608:Kainic Acid / Q000494:pharmacology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism* / Q000494:pharmacology; D017966:Pyramidal Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics / Q000378:metabolism*
chemical_list: D002120:Calcium Channel Agonists; D019837:Ryanodine Receptor Calcium Release Channel; D009569:Nitric Oxide; D007608:Kainic Acid; D002118:Calcium
keywords: Calcium; Neurodegeneration; Nitric oxide; Ryanodine receptor; Seizures