title: Activation of a novel injury-induced calcium-permeable channel that plays a key role in causing extended neuronal depolarization and initiating neuronal death in excitotoxic neuronal injury.
abstract: Protracted elevation in intracellular calcium caused by the activation of the N-methyl-d-aspartate receptor is the main cause of glutamate excitotoxic injury in stroke. However, upon excitotoxic injury, despite the presence of calcium entry antagonists, calcium unexpectedly continues to enter the neuron, causing extended neuronal depolarization and culminating in neuronal death. This phenomenon is known as the calcium paradox of neuronal death in stroke, and it represents a major problem in developing effective therapies for the treatment of stroke. To investigate this calcium paradox and to determine the source of this unexpected calcium entry after neuronal injury, we evaluated whether glutamate excitotoxicity activates an injury-induced calcium-permeable channel responsible for conducting a calcium current that underlies neuronal death. We used a combination of whole-cell and single-channel patch-clamp recordings, fluorescent calcium imaging, and neuronal cell death assays in a well characterized primary hippocampal neuronal culture model of glutamate excitotoxicity/stroke. Here, we report activation of a novel calcium-permeable channel upon excitotoxic glutamate injury that carries calcium current even in the presence of calcium entry inhibitors. Blocking this injury-induced calcium-permeable channel for a significant time period after the initial injury is still effective in preventing calcium entry, extended neuronal depolarization, and delayed neuronal death, thereby accounting for the calcium paradox. This injury-induced calcium-permeable channel represents a major source for the initial calcium entry following stroke, and it offers a new target for extending the therapeutic window for preventing neuronal death after the initial excitotoxic (stroke) injury.
authors.affiliation: Department of Neurology, Virginia Common-wealth University, School of Medicine, Richmond, VA 23298, USA.
authors.forename: Laxmikant S
authors.initials: LS
authors.lastname: Deshpande
authors.forename: David D
authors.initials: DD
authors.lastname: Limbrick
authors.forename: Sompong
authors.initials: S
authors.lastname: Sombati
authors.forename: Robert J
authors.initials: RJ
authors.lastname: DeLorenzo
mesh_terms: D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000502:physiology*; D002478:Cells, Cultured; D002712:Chlorides / Q000494:pharmacology; D003035:Cobalt / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D017097:Electric Impedance; D005013:Ethosuximide / Q000494:pharmacology; D005682:Gadolinium / Q000494:pharmacology; D018698:Glutamic Acid / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D009543:Nifedipine / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D012964:Sodium / Q000378:metabolism / Q000494:pharmacology; D020521:Stroke / Q000503:physiopathology; D017967:Zinc Compounds / Q000494:pharmacology; D020960:omega-Conotoxins / Q000494:pharmacology
chemical_list: D002121:Calcium Channel Blockers; D015220:Calcium Channels; D002712:Chlorides; D017967:Zinc Compounds; D020960:omega-Conotoxins; D003035:Cobalt; D018698:Glutamic Acid; D005013:Ethosuximide; D016291:Dizocilpine Maleate; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; C016837:zinc chloride; D012964:Sodium; D005682:Gadolinium; C018021:cobaltous chloride; D009543:Nifedipine; C038958:gadolinium chloride; D002118:Calcium