Specificity protein 4 functionally regulates the transcription of NMDA receptor subunits GluN1, GluN2A, and GluN2B
Open accessAbstract
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.
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The prioritised fine-mapped set contained 4 genes implicated in developmental disorder: BCL11B, CACNA1C, GRIN2A, and SLC39A8.
“The prioritised fine-mapped set also contained 4 genes implicated in DD; a transcriptional regulator (BCL11B), the well-known CACNA1C38, and genes mentioned elsewhere in this paper (GRIN2A and SLC39A8).”
From Mapping genomic loci implicates genes and synaptic biology in schizophrenia (2022) · cites this paper as [38]
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Cites
Wu, Z., Puigserver, P., Andersson, U., Zhang, C., Adelmant, G., Mootha, V., Troy, A., Cinti, S., Lowell, B., Scarpulla, R. C., et al. (1999) · Cell · doi:10.1016/s0092-8674(00)80611-x · Cited by 4,139 · see citing works
Hollmann, M., & Heinemann, S. F. (1994) · Annual Review of Neuroscience · doi:10.1146/annurev.ne.17.030194.000335 · Cited by 4,011 · see citing works
Molecular diversity of glutamate receptors and implications for brain function
Nakanishi, S. (1992) · Science · doi:10.1126/science.1329206 · Cited by 2,543 · see citing works
Genetic enhancement of learning and memory in mice
Tang, Y., Shimizu, E., Dubé, G., Rampon, C., Kerchner, G. A., Zhuo, M., Liu, G., & Tsien, J. Z. (1999) · Nature · doi:10.1038/43432 · Cited by 1,867 · see citing works
NMDA receptor subunits: diversity, development and disease
Cull-Candy, S., Brickley, S., & Farrant, M. (2001) · Current Opinion in Neurobiology · doi:10.1016/s0959-4388(00)00215-4 · Cited by 1,694 · see citing works
Synaptic versus extrasynaptic NMDA receptor signalling: implications for neurodegenerative disorders
Hardingham, G. E., & Bading, H. (2010) · Nature Reviews Neuroscience · doi:10.1038/nrn2911 · Cited by 1,644 · cited 2× · see citing works
“Extra-synaptic GluN1/GluN2B receptors, however, are pro-apoptotic [43].”
Cytochrome oxidase: an endogenous metabolic marker for neuronal activity
Wong-Riley, M. T. T. (1989) · Trends in Neurosciences · doi:10.1016/0166-2236(89)90165-3 · Cited by 1,238 · see citing works
Self-citationThe Sp-family of transcription factors
Suske, G. (1999) · Gene · doi:10.1016/s0378-1119(99)00357-1 · Cited by 1,112 · see citing works
N-methyl-D-aspartic acid receptor structure and function
McBain, C. J., & Mayer, M. L. (1994) · Physiological Reviews · doi:10.1152/physrev.1994.74.3.723 · Cited by 976 · see citing works
Tovar, K. R., & Westbrook, G. L. (1999) · Journal of Neuroscience · doi:10.1523/jneurosci.19-10-04180.1999 · Cited by 786 · see citing works
Liu, Y., Wong, T. P., Aarts, M., Rooyakkers, A., Liu, L., Lai, T. W., Wu, D. C., Lu, J., Tymianski, M., Craig, A. M., et al. (2007) · The Journal of Neuroscience · doi:10.1523/jneurosci.0116-07.2007 · Cited by 773 · see citing works
Massey, P. V., Johnson, B. E., Moult, P. R., Auberson, Y. P., Brown, M. W., Molnár, E., Collingridge, G. L., & Bashir, Z. I. (2004) · Journal of Neuroscience · doi:10.1523/jneurosci.1697-04.2004 · Cited by 693 · see citing works
Importance of the Intracellular Domain of NR2 Subunits for NMDA Receptor Function In Vivo
Sprengel, R., Suchanek, B., Amico, C., Brusa, R., Burnashev, N., Rozov, A. V., Hvalby, Ø., Jensen, V., Paulsen, O., Andersen, P. N., et al. (1998) · Cell · doi:10.1016/s0092-8674(00)80921-6 · Cited by 460 · see citing works
Sp1 Phosphorylation and Its Regulation of Gene Transcription
Tan, N. Y., & Khachigian, L. M. (2009) · Molecular and Cellular Biology · doi:10.1128/mcb.01828-08 · Cited by 344 · see citing works
Bartlett, T. E., Bannister, N. J., Collett, V. J., Amici-Dargan, S., Massey, P. V., Bortolotto, Z. A., Fitzjohn, S. M., Bashir, Z. I., Collingridge, G. L., & Lodge, D. (2006) · Neuropharmacology · doi:10.1016/j.neuropharm.2006.07.013 · Cited by 266 · see citing works
Preparation of Nuclear and Cytoplasmic Extracts from Mammalian Cells
Abmayr, S. M., Yao, T., Parmely, T. J., & Workman, J. L. (2006) · Current Protocols in Molecular Biology · doi:10.1002/0471142727.mb1201s75 · Cited by 252 · see citing works
Sp3 encodes multiple proteins that differ in their capacity to stimulate or repress transcription
Kennett, S. B. (1997) · Nucleic Acids Research · doi:10.1093/nar/25.15.3110 · Cited by 247 · see citing works
Measurement of the binding of transcription factor Sp1 to a single GC box recognition sequence
Letovsky, J., & Dynan, W. S. (1989) · Nucleic Acids Research · doi:10.1093/nar/17.7.2639 · Cited by 236 · see citing works
Distinct Roles of NR2A and NR2B Cytoplasmic Tails in Long-Term Potentiation
Foster, K. A., McLaughlin, N., Edbauer, D., Phillips, M., Bolton, A., Constantine-Paton, M., & Sheng, M. (2010) · The Journal of Neuroscience · doi:10.1523/jneurosci.4022-09.2010 · Cited by 219 · see citing works
Dhar, S. S., Ongwijitwat, S., & Wong-Riley, M. T. T. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m707587200 · Cited by 188 · see citing works
Self-citationA Critical Role for GluN2B-Containing NMDA Receptors in Cortical Development and Function
Wang, C.-C., Held, R. G., Chang, S.-C., Yang, L., Delpire, E., Ghosh, A., & Hall, B. J. (2011) · Neuron · doi:10.1016/j.neuron.2011.09.023 · Cited by 180 · see citing works
Interactions between the NR2B Receptor and CaMKII Modulate Synaptic Plasticity and Spatial Learning
Zhou, Y., Takahashi, E., Li, W., Halt, A., Wiltgen, B., Ehninger, D., Li, G.-D., Hell, J. W., Kennedy, M. B., & Silva, A. J. (2007) · The Journal of Neuroscience · doi:10.1523/jneurosci.4486-07.2007 · Cited by 179 · see citing works
Supp, D. M., Witte, D. P., Branford, W. W., Smith, E. P., & Potter, S. S. (1996) · Developmental Biology · doi:10.1006/dbio.1996.0134 · Cited by 170 · see citing works
Determination of NMDA NR1 subunit copy number in recombinant NMDA receptors
Béhé, P., Stern, P., Wyllie, D. J. A., Nassar, M. A., Schoepfer, R., & Colquhoun, D. (1995) · Proceedings of the Royal Society B Biological Sciences · doi:10.1098/rspb.1995.0197 · Cited by 139 · see citing works
Increased NR2A:NR2B ratio compresses long-term depression range and constrains long-term memory
Cui, Z., Feng, R., Jacobs, S., Duan, Y., Wang, H., Cao, X., & Tsien, J. Z. (2013) · Scientific Reports · doi:10.1038/srep01036 · Cited by 108 · see citing works
Ongwijitwat, S., & Wong‐Riley, M. T. T. (2005) · Gene · doi:10.1016/j.gene.2005.06.015 · Cited by 108 · see citing works
Self-citationOngwijitwat, S., Liang, H., Graboyes, E. M., & Wong‐Riley, M. T. T. (2006) · Gene · doi:10.1016/j.gene.2006.01.009 · Cited by 108 · see citing works
Self-citationExcitatory Glycine Responses of CNS Myelin Mediated by NR1/NR3 “NMDA” Receptor Subunits
Piña-Crespo, J., Talantova, M. V., Micu, I., States, B. A., Chen, H.-S. V., Tu, S., Nakanishi, N., Tong, G., Zhang, D., Heinemann, S. F., et al. (2010) · Journal of Neuroscience · doi:10.1523/jneurosci.1593-10.2010 · Cited by 102 · see citing works
Dhar, S. S., & Wong‐Riley, M. T. T. (2009) · Journal of Neuroscience · doi:10.1523/jneurosci.3704-08.2009 · Cited by 85 · see citing works
Self-citationZhou, X., Long, J. M., Geyer, M. A., Masliah, E., Kelsoe, J. R., Wynshaw-Boris, A. J., & Chien, K. R. (2004) · Molecular Psychiatry · doi:10.1038/sj.mp.4001621 · Cited by 84 · see citing works
Okamoto, S., Sherman, K., Bai, G., & Lipton, S. A. (2002) · Molecular Brain Research · doi:10.1016/s0169-328x(02)00440-0 · Cited by 77 · see citing works
Interaction Between CaMKII and GluN2B Controls ERK-Dependent Plasticity
Gaamouch, F. E., Buisson, A., Moustié, O., Lemieux, M., Labrecque, S., Bontempi, B., Koninck, P. D., & Nicole, O. (2012) · Journal of Neuroscience · doi:10.1523/jneurosci.5622-11.2012 · Cited by 73 · see citing works
Klein, M., Pieri, I., Uhlmann, F., Pfizenmaier, K., & Eisel, U. L. M. (1998) · Gene · doi:10.1016/s0378-1119(98)00005-5 · Cited by 71 · see citing works
Choo, A. M., Geddes‐Klein, D. M., Hockenberry, A. J., Scarsella, D., Mesfin, M. N., Singh, P. K., Patel, T. P., & Meaney, D. F. (2012) · Neurochemistry International · doi:10.1016/j.neuint.2012.02.007 · Cited by 65 · see citing works
Mao, X. R., Yang, S., Simpkins, J. W., & Barger, S. W. (2006) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2006.04297.x · Cited by 49 · see citing works
Functional Analysis of the Rat N-Methyl-D-aspartate Receptor 2A Promoter
Liu, A., Zhuang, Z.-Y., Hoffman, P. W., & Bai, G. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m211165200 · Cited by 43 · see citing works
Yang, S. J., Liang, H., Ning, G., & Wong‐Riley, M. T. T. (2004) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2004.03250.x · Cited by 34 · see citing works
Self-citationSowa, Y., Shiio, Y., Fujita, T., et al. (1997) · PubMed · Cited by 33 · see citing works
Identification of a novel Sp1 splice variant as a strong transcriptional activator
Infantino, V., Convertini, P., Iacobazzi, F., Pisano, I., Scarcia, P., & Iacobazzi, V. (2011) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2011.07.047 · Cited by 31 · see citing works
Dhar, S. S., Liang, H., & Wong‐Riley, M. T. T. (2009) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2009.07.001 · Cited by 30 · see citing works
Self-citationRegulation of neurotrophin‐3 gene transcription by Sp3 and Sp4 in neurons
Ishimaru, N., Tabuchi, A., Hara, D., Hayashi, H., Sugimoto, T., Yasuhara, M., Shiota, J., & Tsuda, M. (2006) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2006.04216.x · Cited by 29 · see citing works
Sp1 and AP2 enhance promoter activity of the mouse GM3-synthase gene
Xia, T., Zeng, G., Gao, L., & Yu, R. K. (2005) · Gene · doi:10.1016/j.gene.2005.03.010 · Cited by 26 · see citing works
Functional analysis of the rat cytochrome c oxidase subunit 6A1 promoter in primary neurons
Ongwijitwat, S., & Wong‐Riley, M. T. T. (2004) · Gene · doi:10.1016/j.gene.2004.04.024 · Cited by 22 · see citing works
Self-citationPriya, A., Johar, K., & Wong‐Riley, M. T. T. (2012) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2012.10.014 · Cited by 20 · see citing works
Self-citationDhar, S. S., Johar, K., & Wong‐Riley, M. T. T. (2013) · Open Biology · doi:10.1098/rsob.120176 · Cited by 19 · see citing works
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Mapping genomic loci implicates genes and synaptic biology in schizophrenia
Trubetskoy, V., Pardiñas, A. F., Qi, T., Panagiotaropoulou, G., Awasthi, S., Bigdeli, T. B., Bryois, J., Chen, C.-Y., Dennison, C. A., Hall, L. S., et al. (2022) · Nature · doi:10.1038/s41586-022-04434-5 · Cited by 2,964 · see citing works
- Authors
- Priya, A., Johar, K., & Wong-Riley, M. T. T.
- Affiliations
- Medical College of Wisconsin (US)
- ORCID
- Johar, Kaid
- Venue
- Biochimica et Biophysica Acta (BBA) - Molecular Cell Research
- Publisher
- Elsevier BV
- Published
- 2013-12
- Volume
- 1833
- Issue
- 12
- Pages
- 2745-2756
- ISSN
- 0167-4889 (ISSN-L)
- PMC
- PMC3834217
- OpenAlex
- W2013878988
- Cited by
- 33
- References
- 45
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 2 · 2023: 1 · 2022: 4 · 2021: 2 · 2020: 2 · 2019: 2 · 2017: 2 · 2016: 2 · 2015: 6 · 2014: 5 · 2013: 2
- FWCI
- 2.45
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Biochimica et Biophysica Acta (BBA) - Molecular Cell Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIH (R01 EY018441)
- NIH/NEI (1-T32-EY14537)
- NIGMS (GM080202)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Keywords
- Sp4, NMDA receptor, GluN1, GluN2A, GluN2B, GluN2C, transcriptional regulation, nuclear respiratory factors, NRF1, Nrf2, cytochrome c oxidase, neuronal energy metabolism, glutamatergic neurotransmission, Sp1, Sp3
- MeSH terms
- Animals, Binding Sites, Carrier Proteins, Cell Nucleus, Cells, Cultured, Computer Simulation, HeLa Cells, Humans, Membrane Potentials, Mutation, Nerve Tissue Proteins, Neurons, Potassium Chloride, Promoter Regions, Genetic, Protein Binding, Tetrodotoxin, Transcription, Genetic, Visual Cortex, Receptors, N-Methyl-D-Aspartate, Sp1 Transcription Factor, Gene Silencing, Chromatin Immunoprecipitation, Mutant Proteins, Mice, Sp3 Transcription Factor, Sp4 Transcription Factor
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