Coupling of energy metabolism and synaptic transmission at the transcriptional level: role of nuclear respiratory factor 1 in regulating both cytochrome c oxidase and NMDA glutamate receptor subunit genes. J Neurosci 2009 Jan 14;29(2):483-92
Date
01/16/2009Pubmed ID
19144849Pubmed Central ID
PMC2775551DOI
10.1523/JNEUROSCI.3704-08.2009Scopus ID
2-s2.0-58849149820 (requires institutional sign-in at Scopus site) 70 CitationsAbstract
Neuronal activity and energy metabolism are tightly coupled processes. Regions high in neuronal activity, especially of the glutamatergic type, have high levels of cytochrome c oxidase (COX). Perturbations in neuronal activity affect the expressions of COX and glutamatergic NMDA receptor subunit 1 (NR1). The present study sought to test our hypothesis that the coupling extends to the transcriptional level, whereby NR1 and possibly other NR subunits and COX are coregulated by the same transcription factor, nuclear respiratory factor 1 (NRF-1), which regulates all COX subunit genes. By means of multiple approaches, including in silico analysis, electrophoretic mobility shift and supershift assays, in vivo chromatin immunoprecipitation, promoter mutations, and real-time quantitative PCR, NRF-1 was found to functionally bind to the promoters of Grin 1 (NR1), Grin 2b (NR2b) and COX subunit genes, but not of Grin2a and Grin3a genes. These transcripts were upregulated by KCl and downregulated by tetrodotoxin (TTX) in cultured primary neurons. However, silencing of NRF-1 with small interference RNA blocked the upregulation of Grin1, Grin2b, and COX induced by KCl, and overexpression of NRF-1 rescued these transcripts that were suppressed by TTX. NRF-1 binding sites on Grin1 and Grin2b genes are also highly conserved among mice, rats, and humans. Thus, NRF-1 is an essential transcription factor critical in the coregulation of NR1, NR2b, and COX, and coupling exists at the transcriptional level to ensure coordinated expressions of proteins important for synaptic transmission and energy metabolism.
Author List
Dhar SS, Wong-Riley MTMESH terms used to index this publication - Major topics in bold
AnimalsAnimals, Newborn
Cells, Cultured
Cerebral Cortex
Chromatin Immunoprecipitation
Electron Transport Complex IV
Electrophoretic Mobility Shift Assay
Energy Metabolism
Gene Expression Regulation
Humans
Mice
Mutation
Neuroblastoma
Neurons
Nuclear Respiratory Factor 1
Potassium Chloride
Promoter Regions, Genetic
Protein Binding
Protein Subunits
RNA, Messenger
RNA, Small Interfering
Rats
Receptors, N-Methyl-D-Aspartate
Sodium Channel Blockers
Synaptic Transmission
Tetrodotoxin
Transfection