title: Nitric oxide promotes intracellular calcium release from mitochondria in striatal neurons.
abstract: Overproduction of nitric oxide by NMDA receptor stimulation is implicated in calcium deregulation and neurodegeneration of striatal neurons. We investigated the involvement of nitric oxide (NO) in inducing intracellular calcium release and in modifying calcium transients evoked by NMDA. NO application (4-10 microM) reversibly and repeatedly increased the intracellular calcium concentration [Ca2+]i in Fura-2- or fluo-3-loaded cultured mouse striatal neurons. NO-induced [Ca2+]i responses persisted in the absence of extracellular calcium, indicating that Ca2+ was released from intracellular stores. The source of calcium was distinct from [Ca2+]i-activated (ruthenium red and ryanodine sensitive) or IP3-activated (thapsigargin-sensitive) Ca2+ stores and was not dependent on cGMP production because a cell permeant analog, 8-bromo-cGMP, did not increase basal [Ca2+]i. Glucose removal potentiated the NO-induced release of [Ca2+]i. In contrast, pretreatment with either the mitochondrial uncoupler carbonyl cyanide m-chlorophenylhydrazone or cyclosporin A, a blocker of the mitochondrial permeability transition pore, prevented the [Ca2+]i increase after NO. The rise in [Ca2+]i during NO exposure was preceded by a decrease in mitochondrial membrane potential that was partly reversible during washout. Repeated applications of NMDA induced irreversible [Ca2+]i responses in a subpopulation of striatal cells that were greatly reduced by the NOS inhibitor N omega-nitro-l-arginine. Calcium transients were prolonged by conjoint application of NMDA and NO. We conclude that NMDA-evoked [Ca2+]i transients are modulated by endogenous NO production, which leads to release of calcium from the mitochondrial pool. An NO-activated mitochondrial permeability transition pore may lead to cell death after overstimulation of NMDA receptors.
authors.affiliation: Institute for Medical Neurobiology, University of Magdeburg, Germany. thomas.horn@medizin.uni-magdeburg.de
authors.forename: Thomas F W
authors.initials: TF
authors.lastname: Horn
authors.forename: Gerald
authors.initials: G
authors.lastname: Wolf
authors.forename: Steven
authors.initials: S
authors.lastname: Duffy
authors.forename: Samuel
authors.initials: S
authors.lastname: Weiss
authors.forename: Gerburg
authors.initials: G
authors.lastname: Keilhoff
authors.forename: Brian A
authors.initials: BA
authors.lastname: MacVicar
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone / Q000494:pharmacology; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D016572:Cyclosporine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005947:Glucose / Q000378:metabolism; D051379:Mice; D018613:Microscopy, Confocal; D008928:Mitochondria / Q000378:metabolism*; D016202:N-Methylaspartate / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D019284:Thapsigargin / Q000494:pharmacology
chemical_list: D009573:Nitrites; D009569:Nitric Oxide; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone; D016202:N-Methylaspartate; D019284:Thapsigargin; D016572:Cyclosporine; D019001:Nitric Oxide Synthase; D006152:Cyclic GMP; D005947:Glucose; D002118:Calcium