RRC ID 43777
Author Fukumori R, Takarada T, Kambe Y, Nakazato R, Fujikawa K, Yoneda Y.
Title Possible involvement of mitochondrial uncoupling protein-2 in cytotoxicity mediated by acquired N-methyl-D-aspartate receptor channels.
Journal Neurochem. Int.
Abstract We have previously shown the possible involvement of mitochondrial membrane potential disruption in the mechanisms underlying the neurotoxicity seen after activation of N-methyl-d-aspartate (NMDA) receptors (NMDAR) in primary cultured rat hippocampal neurons. In this study, we attempted to demonstrate a pivotal role of mitochondrial uncoupling protein-2 (UCP2) as a determinant of the NMDA neurotoxicity by using acquired NMDAR channels artificially orchestrated in HEK293 cells. In cells with overexpression of UCP2, immunoreactive UCP2 was exclusively detected at intracellular locations stained with the mitochondrial marker MitoTracker. In cells with acquired NMDAR channels, exposure to either NMDA or the calcium ionophore A23187 similarly led to a significant increase in cytosolic Ca(2+) levels determined by Fluo-3 imaging irrespective of the overexpression of UCP2. By contrast, NMDA, but not A23187, was significantly more effective in increasing mitochondrial Ca(2+) levels determined by Rhod-2 fluorescence imaging in cells transfected with NMDAR subunit and UCP2 expression vectors than in those without UCP2 overexpression. Overexpression of UCP2 significantly increased the number of cells stained with propidium iodide in cultures with acquired NMDAR channels, but failed to significantly affect that in cells exposed to A23187. Immunocytochemical and immunoprecipitation analyses similarly revealed the possible interaction between GluN1 subunit and UCP2 in HEK293 cells with acquired NMDAR channels and UCP2 overexpression. These results suggest that UCP2 could play a role as a determinant of the neurotoxicity mediated by NMDAR through a mechanism related to the unidentified interaction with the essential GluN1 subunit toward modulation of mitochondrial Ca(2+) levels in neurons.
Volume 61(4)
Pages 498-505
Published 2012-9
DOI 10.1016/j.neuint.2012.03.019
PII S0197-0186(12)00121-0
PMID 22490607
MeSH Calcimycin / pharmacology Calcium / metabolism HEK293 Cells Humans Immunohistochemistry Ion Channels / physiology* Mitochondria / metabolism Mitochondrial Proteins / physiology* Receptors, N-Methyl-D-Aspartate / metabolism* Uncoupling Protein 2
IF 3.603
Times Cited 3
WOS Category NEUROSCIENCES BIOCHEMISTRY & MOLECULAR BIOLOGY
Resource
Human and Animal Cells