title: Specificity protein 4 functionally regulates the transcription of NMDA receptor subunits GluN1, GluN2A, and GluN2B.
abstract: N-Methyl-d-aspartate (NMDA) receptors are major glutamatergic receptors involved in most excitatory neurotransmission in the brain. The transcriptional regulation of NMDA receptors is not fully understood. Previously, we found that the GluN1 and GluN2B subunits of the NMDA receptor are regulated by nuclear respiratory factors 1 and 2 (NRF-1 and NRF-2). NRF-1 and NRF-2 also regulate all 13 subunits of cytochrome c oxidase (COX), a critical energy-generating enzyme, thereby coupling neuronal activity and energy metabolism at the transcriptional level. Specificity protein (Sp) is a family of transcription factors that bind to GC-rich regions, with Sp1, Sp3, and Sp4 all binding to the same cis- motifs. Sp1 and Sp3 are ubiquitously expressed, whereas Sp4 expression is restricted to neurons and testicular cells. Recently, we found that the Sp1 factor regulates all subunits of COX. The goal of the present study was to test our hypothesis that the Sp factors also regulate specific subunits of NMDA receptors, and that they function with NRF-1 and NRF-2 via one of three mechanisms: complementary, concurrent and parallel, or a combination of complementary and concurrent/parallel. By means of multiple approaches we found that Sp4 functionally regulated GluN1, GluN2A, and GluN2B, but not GluN2C. On the other hand, Sp1 and Sp3 did not regulate these subunits as previously thought. Our data suggest that Sp4 operates in a complementary and concurrent/parallel manner with NRF-1 and NRF-2 to mediate the tight coupling between energy metabolism and neuronal activity at the molecular level.
authors.affiliation: Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.
authors.forename: Anusha
authors.initials: A
authors.lastname: Priya
authors.affiliation: Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.
authors.forename: Kaid
authors.initials: K
authors.lastname: Johar
authors.affiliation: Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA. Electronic address: mwr@mcw.edu.
authors.forename: Margaret T T
authors.initials: MTT
authors.lastname: Wong-Riley
mesh_terms: D000818:Animals; D001665:Binding Sites; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D003198:Computer Simulation; D020868:Gene Silencing / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D011189:Potassium Chloride / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics* / Q000378:metabolism; D016329:Sp1 Transcription Factor / Q000378:metabolism; D051705:Sp3 Transcription Factor / Q000378:metabolism; D051706:Sp4 Transcription Factor / Q000378:metabolism*; D013779:Tetrodotoxin / Q000633:toxicity; D014158:Transcription, Genetic / Q000187:drug effects; D014793:Visual Cortex / Q000166:cytology
chemical_list: D002352:Carrier Proteins; D050505:Mutant Proteins; D009419:Nerve Tissue Proteins; D011189:Potassium Chloride; D016194:Receptors, N-Methyl-D-Aspartate; D016329:Sp1 Transcription Factor; D051705:Sp3 Transcription Factor; D051706:Sp4 Transcription Factor; D013779:Tetrodotoxin; C121673:Gprin1 protein, mouse; C121001:NR2B NMDA receptor; C497125:Sp4 protein, mouse
keywords: Gene name for NMDA receptor; Gene regulation; GluN1; GluN2A; GluN2B; Grin; NMDA; Sp; Sp4; Specificity protein transcription factor