Nuclear respiratory factor 1 co-regulates AMPA glutamate receptor subunit 2 and cytochrome c oxidase: tight coupling of glutamatergic transmission and energy metabolism in neurons.
Neuronal activity, especially of the excitatory glutamatergic type, is highly dependent on energy from the oxidative pathway. We hypothesized that the coupling existed at the transcriptional level by having the same transcription factor to regulate a marker of energy metabolism, cytochrome c oxidase (COX) and an important subunit of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid glutamate receptors, GluR2 (Gria2). Nuclear respiratory factor 1 (NRF-1) was a viable candidate because it regulates all COX subunits and potentially activates Gria2. By means of in silico analysis, electrophoretic mobility shift and supershift, chromatin immunoprecipitation, and promoter mutational assays, we found that NRF-1 functionally bound to Gria2 promoter. Silencing of NRF-1 with small interference RNA prevented the depolarization-stimulated up-regulation of Gria2 and COX, and over-expression of NRF-1 rescued neurons from tetrodotoxin-induced down-regulation of Gria2 and COX transcripts. Thus, neuronal activity and energy metabolism are tightly coupled at the molecular level, and NRF-1 is a critical agent in this process.
Dhar
Shilpa S
SS
Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
Liang
Huan Ling
HL
Wong-Riley
Margaret T T
MT
D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation / Q000379:methods; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D003576:Electron Transport Complex IV / Q000378:metabolism*; D024202:Electrophoretic Mobility Shift Assay / Q000379:methods; D004734:Energy Metabolism / Q000502:physiology*; D007546:Isoquinolines / Q000378:metabolism; D051379:Mice; D016296:Mutagenesis / Q000502:physiology; D009447:Neuroblastoma; D009474:Neurons / Q000378:metabolism*; D051266:Nuclear Respiratory Factor 1 / Q000378:metabolism*; D011189:Potassium Chloride / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000502:physiology; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000378:metabolism*; D014162:Transfection; D014793:Visual Cortex / Q000166:cytology
D007546:Isoquinolines; D051266:Nuclear Respiratory Factor 1; D034741:RNA, Small Interfering; D018091:Receptors, AMPA; D011189:Potassium Chloride; C017475:lucifer yellow; D051546:Cyclooxygenase 2; C489691:Ptgs2 protein, rat; D003576:Electron Transport Complex IV; C104722:glutamate receptor ionotropic, AMPA 2