title: Comparative impact of voltage-gated calcium channels and NMDA receptors on mitochondria-mediated neuronal injury.
abstract: Glutamate excitotoxicity, a major component of many neurodegenerative disorders, is characterized by excessive calcium influx selectively through NMDARs. However, there is a substantial uncertainty concerning why other known routes of significant calcium entry, in particular, VGCCs, are not similarly toxic. Here, we report that in the majority of neurons in rat hippocampal and cortical cultures, maximal L-type VGCC activation induces much lower calcium loading than toxic NMDAR activation. Consequently, few depolarization-activated neurons exhibit calcium deregulation and cell death. Activation of alternative routes of calcium entry induced neuronal death in proportion to the degree of calcium loading. In a small subset of neurons, depolarization evoked stronger calcium elevations, approaching those induced by toxic NMDA. These neurons were characterized by elevated expression of VGCCs and enhanced voltage-gated calcium currents, mitochondrial dysfunction and cell death. Preventing VGCC-dependent mitochondrial calcium loading resulted in stronger cytoplasmic calcium elevations, whereas inhibiting mitochondrial calcium clearance accelerated mitochondrial depolarization. Both observations further implicate mitochondrial dysfunction in VGCC-mediated cell death. Results indicate that neuronal vulnerability tracks the extent of calcium loading but does not appear to depend explicitly on the route of calcium entry.
authors.affiliation: Laboratory of Neurobiology, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Ruslan I
authors.initials: RI
authors.lastname: Stanika
authors.forename: Idalis
authors.initials: I
authors.lastname: Villanueva
authors.forename: Galina
authors.initials: G
authors.lastname: Kazanina
authors.forename: S Brian
authors.initials: SB
authors.lastname: Andrews
authors.forename: Natalia B
authors.initials: NB
authors.lastname: Pivovarova
mesh_terms: D000818:Animals; D002118:Calcium / Q000502:physiology; D015220:Calcium Channels / Q000502:physiology*; D016923:Cell Death / Q000502:physiology; D002478:Cells, Cultured; D008928:Mitochondria / Q000473:pathology / Q000502:physiology*; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*
chemical_list: D015220:Calcium Channels; D016194:Receptors, N-Methyl-D-Aspartate; D002118:Calcium