The molecular events occur during MK-801-induced cytochrome oxidase subunit II down-regulation in GT1-7 cells.
Previously, we showed that predominant expression of the N-methyl-D-aspartate (NMDA) receptor in the neurons of the sexually dimorphic nucleus of the preoptic area of male rats plays an important role in preventing neurons from apoptosis during sexual development. Blocking of the NMDA receptor by dizocilpine ((+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d] cyclohepten-5,10-iminemaleate (MK-801) causes down-regulation of some survival-related genes including cytochrome oxidase subunit II (COII), a mitochondria-encoded complex IV subunit, which in turn induces ATP depletion and the occurrence of apoptosis. The aim of this study is to investigate the molecular events during down-regulation of the COII gene expression induced by blocking of the NMDA receptor. Treatment of the GnRH cell line (GT1-7) with MK-801 caused 1) a decrease of intracellular calcium concentration ([Ca2+]i) after 20 h; 2) significant decreases of the levels of peroxisome proliferator-activated receptor coactivator-1 (PGC-1) mRNA and protein after 24 h; 3) down-regulation of COII mRNA after 36 h; and 4) the occurrence of neuronal apoptosis after 48 h. Accordingly, we hypothesize that blocking of the NMDA receptor may cause a decrease of the [Ca2+]i, which in turn inhibits the expressions of PGC-1 and COII and then leads to subsequent neuronal apoptosis.
Lee
Tzu-Ying
TY
College of Medicine, Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan, ROC. wslee@tmu.edu.tw
Tsai
Ke-Li
KL
Lee
Wen-Sen
WS
Hsu
Chin
C
D002118:Calcium / Q000502:physiology; D002460:Cell Line; D017931:DNA Primers; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects; D003576:Electron Transport Complex IV / Q000235:genetics*; D005434:Flow Cytometry; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006801:Humans; D009474:Neurons / Q000502:physiology; D009687:Nuclear Proteins / Q000302:isolation & purification; D021122:Protein Subunits / Q000235:genetics; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D020133:Reverse Transcriptase Polymerase Chain Reaction
D017931:DNA Primers; D009687:Nuclear Proteins; D021122:Protein Subunits; D012313:RNA; D016291:Dizocilpine Maleate; D003576:Electron Transport Complex IV; D002118:Calcium