Ca 2+ and Na + dependence of 3-hydroxyglutarate-induced excitotoxicity in primary neuronal cultures from chick embryo telencephalons

• Verfasst von: Kölker, Stefan [VerfasserIn]
• Verfasst von: Koehr, Georg [VerfasserIn]
• Verfasst von: Ahlemeyer, Barbara [VerfasserIn]
• Verfasst von: Okun, Jürgen G. [VerfasserIn]
• Verfasst von: Pawlak, Verena [VerfasserIn]
• Verfasst von: Hörster, Friederike [VerfasserIn]
• Verfasst von: Mayatepek, Ertan [VerfasserIn]
• Verfasst von: Krieglstein, Josef [VerfasserIn]
• Verfasst von: Hoffmann, Georg F. [VerfasserIn]
• Titel: Ca 2+ and Na + dependence of 3-hydroxyglutarate-induced excitotoxicity in primary neuronal cultures from chick embryo telencephalons
• Verf.angabe: Stefan Kölker, Georg Köhr, Barbara Ahlemeyer, Jürgen G. Okun, Verena Pawlak, Friederike Hörster, Ertan Mayatepek, Josef Krieglstein, Georg F. Hoffmann
• Jahr: 2002
• Umfang: 8 S.
• Fussnoten: Im Titel sind "2+" und "+" hochgestellt ; Gesehen am 28.12.2020
• Titel Quelle: Enthalten in: Pediatric research
• Ort Quelle: London [u.a.] Nature Publishing Group, 1967
• Jahr Quelle: 2002
• Band/Heft Quelle: 52(2002), 2, Seite 199-206
• ISSN Quelle: 1530-0447
• DOI: doi:10.1203/00006450-200208000-00011
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1743568908

Abstract

Glutaryl-CoA dehydrogenase deficiency (also known as glutaric aciduria type I) is an autosomal, recessively inherited neurometabolic disorder with a distinct neuropathology characterized by acute encephalopathy during a vulnerable period of brain development. Neuronal damage in this disease was demonstrated to involve N-methyl-d-aspartate (NMDA) receptor-mediated neurotoxicity of the endogenously accumulating metabolite 3-hydroxyglutarate (3-OH-GA). However, it remained unclear whether NMDA receptors are directly or indirectly activated and whether 3-OH-GA disturbs the intracellular Ca2+ homeostasis. Here we report that 3-OH-GA activated recombinant NMDA receptors (e.g. NR1/NR2A) but not recombinant α-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptors (e.g. GluR-A/GluR-B) in HEK293 cells. Fluorescence microscopy using fura-2 as Ca2+ indicator revealed that 3-OH-GA increased intracellular Ca2+ concentrations in the presence of extracellular Ca2+ in cultured chick neurons. Similar to glutamate-induced cell damage, 3-OH-GA neurotoxicity was modulated by extracellular Na+. The large cation N-methyl-d-glucamine, which does not permeate NMDA receptor channels, enhanced 3-OH-GA-induced Ca2+ increase and cell damage. In contrast, 3-OH-GA-induced neurotoxicity was reduced after replacement of Na+ by Li+, which permeates NMDA channels but does not affect the Na+/Ca2+ exchanger in the plasma membrane. Spectrophotometric analysis of respiratory chain complexes I-V in submitochondrial particles from bovine heart revealed only a weak inhibition of 3-OH-GA on complex V at the highest concentration tested (10 mM). In conclusion, the present study revealed that NMDA receptor activation and subsequent disturbance of Ca2+ homeostasis contribute to 3-OH-GA-induced cell damage.