title: Activation of voltage-sensitive sodium channels during oxygen deprivation leads to apoptotic neuronal death.
abstract: Sodium (Na(+)) entry into neurons during hypoxia is known to be associated with cell death. However, it is not clear whether Na(+) entry causes cell death and by what mechanisms this increased Na(+) entry induces death. In this study we used cultures of rat neocortical neurons to show that an increase in intracellular sodium (Na(i)(+)) through voltage-sensitive sodium channels (VSSCs), during hypoxia contributes to apoptosis. Hypoxia increased Na(i)(+) and induced neuronal apoptosis, as assessed by electron microscopy, annexin V staining, and terminal UDP nick end labeling staining. Reducing Na(+) entry with the VSSC blocker, tetrodotoxin (TTX), attenuated apoptotic neuronal death via a reduction in caspase-3 activation. Since the attenuation of apoptosis by TTX during hypoxia suggested that the activation of VSSCs and Na(+) entry are crucial events in hypoxia-induced cell death, we also determined whether the activation of VSSCs per se could lead to apoptosis under resting conditions. Increasing Na(+) entry with the VSSC activator veratridine also induced neuronal apoptosis and caspase-3 activation. These data indicate that a) Na(+) entry via VSSCs during hypoxia leads to apoptotic cell death which is mediated, in part, by caspase-3 and b) activation of VSSCs during oxygen deprivation is a major event by which hypoxia induces cell death.
authors.affiliation: Department of Pediatrics, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520-8064, USA. kenneth.banasiak@yale.edu
authors.forename: K J
authors.initials: KJ
authors.lastname: Banasiak
authors.forename: O
authors.initials: O
authors.lastname: Burenkova
authors.forename: G G
authors.initials: GG
authors.lastname: Haddad
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D015687:Cell Hypoxia / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D005260:Female; D002534:Hypoxia, Brain / Q000378:metabolism / Q000473:pathology; D008564:Membrane Potentials / Q000502:physiology; D009474:Neurons / Q000166:cytology* / Q000502:physiology*; D010100:Oxygen / Q000494:pharmacology*; D011247:Pregnancy; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012964:Sodium / Q000378:metabolism; D026941:Sodium Channel Blockers / Q000494:pharmacology; D015222:Sodium Channels / Q000378:metabolism*; D013779:Tetrodotoxin / Q000494:pharmacology; D051028:bcl-2-Associated X Protein
chemical_list: D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D051028:bcl-2-Associated X Protein; D013779:Tetrodotoxin; D012964:Sodium; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D010100:Oxygen