Nuclear respiratory factor 2 regulates the expression of the same NMDA receptor subunit genes as NRF-1: both factors act by a concurrent and parallel mechanism to couple energy metabolism and synaptic transmission. Biochim Biophys Acta 2013 Jan;1833(1):48-58
Date
10/23/2012Pubmed ID
23085505Pubmed Central ID
PMC3518722DOI
10.1016/j.bbamcr.2012.10.014Scopus ID
2-s2.0-84868524736 (requires institutional sign-in at Scopus site) 19 CitationsAbstract
Neuronal activity and energy metabolism are tightly coupled processes. Previously, we found that nuclear respiratory factor 1 (NRF-1) transcriptionally co-regulates energy metabolism and neuronal activity by regulating all 13 subunits of the critical energy generating enzyme, cytochrome c oxidase (COX), as well as N-methyl-d-aspartate (NMDA) receptor subunits 1 and 2B, GluN1 (Grin1) and GluN2B (Grin2b). We also found that another transcription factor, nuclear respiratory factor 2 (NRF-2 or GA-binding protein) regulates all subunits of COX as well. The goal of the present study was to test our hypothesis that NRF-2 also regulates specific subunits of NMDA receptors, and that it functions with NRF-1 via one of three mechanisms: complementary, concurrent and parallel, or a combination of complementary and concurrent/parallel. By means of multiple approaches, including in silico analysis, electrophoretic mobility shift and supershift assays, in vivo chromatin immunoprecipitation of mouse neuroblastoma cells and rat visual cortical tissue, promoter mutations, real-time quantitative PCR, and western blot analysis, NRF-2 was found to functionally regulate Grin1 and Grin2b genes, but not any other NMDA subunit genes. Grin1 and Grin2b transcripts were up-regulated by depolarizing KCl, but silencing of NRF-2 prevented this up-regulation. On the other hand, over-expression of NRF-2 rescued the down-regulation of these subunits by the impulse blocker TTX. NRF-2 binding sites on Grin1 and Grin2b are conserved among species. Our data indicate that NRF-2 and NRF-1 operate in a concurrent and parallel manner in mediating the tight coupling between energy metabolism and neuronal activity at the molecular level.
Author List
Priya A, Johar K, Wong-Riley MTMESH terms used to index this publication - Major topics in bold
AnimalsCells, Cultured
Energy Metabolism
GA-Binding Protein Transcription Factor
Gene Expression Regulation
Humans
Mice
Models, Biological
Neurons
Nuclear Respiratory Factor 1
Promoter Regions, Genetic
Protein Binding
Protein Subunits
Rats
Receptors, N-Methyl-D-Aspartate
Signal Transduction
Synaptic Transmission