The Discovery of Human of GLUD2 Glutamate Dehydrogenase and Its Implications for Cell Function in Health and Disease
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While the evolutionary changes that led to traits unique to humans remain unclear, there is increasing evidence that enrichment of the human genome through DNA duplication processes may have contributed to traits such as bipedal locomotion, higher cognitive abilities and language. Among the genes that arose through duplication in primates during the period of increased brain development was GLUD2, which encodes the hGDH2 isoform of glutamate dehydrogenase expressed in neural and other tissues. Glutamate dehydrogenase GDH is an enzyme central to the metabolism of glutamate, the main excitatory neurotransmitter in mammalian brain involved in a multitude of CNS functions, including cognitive processes. In nerve tissue GDH is expressed in astrocytes that wrap excitatory synapses, where it is thought to play a role in the metabolic fate of glutamate removed from the synaptic cleft during excitatory transmission. Expression of GDH rises sharply during postnatal brain development, coinciding with nerve terminal sprouting and synaptogenesis. Compared to the original hGDH1 (encoded by the GLUD1 gene), which is potently inhibited by GTP generated by the Krebs cycle, hGDH2 can function independently of this energy switch. In addition, hGDH2 can operate efficiently in the relatively acidic environment that prevails in astrocytes following glutamate uptake. This adaptation is thought to provide a biological advantage by enabling enhanced enzyme catalysis under intense excitatory neurotransmission. While the novel protein may help astrocytes to handle increased loads of transmitter glutamate, dissociation of hGDH2 from GTP control may render humans vulnerable to deregulation of this enzyme's function. Here we will retrace the cloning and characterization of the novel GLUD2 gene and the potential implications of this discovery in the understanding of mechanisms that permitted the brain and other organs that express hGDH2 to fine-tune their functions in order to meet new challenging demands. In addition, the potential role of gain-of-function of hGDH2 variants in human neurodegenerative processes will be considered.
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GLUD1 and GLUD2 are involved in energy homeostasis.
“GLUD1 and GLUD2, which are involved in energy homeostasis36,37.”
From Oxytocin pathway gene networks in the human brain (2019) · cites this paper as [37]
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Mitochondria, Oxidants, and Aging
Balaban, R. S., Nemoto, S., & Finkel, T. (2005) · Cell · doi:10.1016/j.cell.2005.02.001 · Cited by 4,388 · see citing works
Phosphorylation of ULK1 (hATG1) by AMP-Activated Protein Kinase Connects Energy Sensing to Mitophagy
Egan, D. F., Shackelford, D. B., Mihaylova, M. M., Gelino, S., Kohnz, R. A., Mair, W., Vasquez, D. S., Joshi, A., Gwinn, D. M., Taylor, R., et al. (2011) · Science · doi:10.1126/science.1196371 · Cited by 2,600 · see citing works
Glutaminolysis Activates Rag-mTORC1 Signaling
Durán, R. V., Oppliger, W., Robitaille, A. M., Heiserich, L., Skendaj, R., Gottlieb, E., & Hall, M. N. (2012) · Molecular Cell · doi:10.1016/j.molcel.2012.05.043 · Cited by 723 · see citing works
Microdomains for neuron–glia interaction: parallel fiber signaling to Bergmann glial cells
Grosche, J., Matyash, V., Möller, T., Verkhratsky, A., Reichenbach, A., & Kettenmann, H. (1999) · Nature Neuroscience · doi:10.1038/5692 · Cited by 700 · see citing works
Stanley, C. A., Lieu, Y. K., Hsu, B. Y. L., Burlina, A., Greenberg, C. R., Hopwood, N. J., Perlman, K., Rich, B. H., Zammarchi, E., & Poncz, M. (1998) · New England Journal of Medicine · doi:10.1056/nejm199805073381904 · Cited by 676 · see citing works
Levy, L. M., Warr, O., & Attwell, D. (1998) · Journal of Neuroscience · doi:10.1523/jneurosci.18-23-09620.1998 · Cited by 490 · see citing works
L-leucine and a nonmetabolized analogue activate pancreatic islet glutamate dehydrogenase
Sener, A., & Malaisse, W. J. (1980) · Nature · doi:10.1038/288187a0 · Cited by 354 · see citing works
Cerebral metabolism of [1,2-13C2]acetate as detected by in vivo and in vitro 13C NMR.
Cerdán, S., Künnecke, B., & Seelig, J. (1990) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)38247-x · Cited by 336 · see citing works
Emergence of Young Human Genes after a Burst of Retroposition in Primates
Marques, A. C., Dupanloup, I., Vinckenbosch, N., Reymond, A., & Kaessmann, H. (2005) · PLoS Biology · doi:10.1371/journal.pbio.0030357 · Cited by 311 · see citing works
Abnormal glutamate metabolism in amyotrophic lateral sclerosis
Plaitakis, A., & Caroscio, J. T. (1987) · Annals of Neurology · doi:10.1002/ana.410220503 · Cited by 306 · see citing works
Self-citationRotenone Model of Parkinson Disease
Panov, A., Dikalov, S., Shalbuyeva, N., Taylor, G., Sherer, T., & Greenamyre, J. T. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m508628200 · Cited by 288 · see citing works
Abnormal Glutamate Metabolism in an Adult-Onset Degenerative Neurological Disorder
Plaitakis, A., Berl, S., & Yahr, M. D. (1982) · Science · doi:10.1126/science.6121377 · Cited by 226 · see citing works
Self-citationNew roles for astrocytes: Regulation of CNS synaptogenesis
Ślęzak, M., & Pfrieger, F. W. (2003) · Trends in Neurosciences · doi:10.1016/j.tins.2003.08.005 · Cited by 224 · see citing works
Birth and adaptive evolution of a hominoid gene that supports high neurotransmitter flux
Burki, F., & Kaessmann, H. (2004) · Nature Genetics · doi:10.1038/ng1431 · Cited by 203 · see citing works
Neurological disorders associated with deficiency of glutamate dehydrogenase
Plaitakis, A., Berl, S., & Yahr, M. D. (1984) · Annals of Neurology · doi:10.1002/ana.410150206 · Cited by 183 · see citing works
Self-citationShashidharan, P., Michaelidis, T. M., Robakis, N. K. R. K., Kresovali, A., Papamatheakis, J. D., & Plaitakis, A. (1994) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)89484-x · Cited by 158 · see citing works
Self-citationMinireview: Role of Glia in Neuroendocrine Function
García‐Segura, L. M., & McCarthy, M. M. (2003) · Endocrinology · doi:10.1210/en.2003-1383 · Cited by 153 · see citing works
Chatton, J., Marquet, P. P., & Magistretti, P. J. (2000) · European Journal of Neuroscience · doi:10.1046/j.1460-9568.2000.00269.x · Cited by 138 · see citing works
The Structure of Apo Human Glutamate Dehydrogenase Details Subunit Communication and Allostery
Smith, T. J., Schmidt, T., Fang, J., Wu, J., Siuzdak, G. E., & Stanley, C. A. (2002) · Journal of Molecular Biology · doi:10.1016/s0022-2836(02)00161-4 · Cited by 130 · see citing works
Stimulation of pancreatic islet metabolism and insulin release by a nonmetabolizable amino acid.
Sener, A., MALAISSE-LAGAE, F., & Malaisse, W. J. (1981) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.78.9.5460 · Cited by 127 · see citing works
Mutant Huntingtin: Nuclear translocation and cytotoxicity mediated by GAPDH
Bae, B.-I., Hara, M. R., Cascio, M. B., Wellington, C. L., Hayden, M. R., Ross, C. A., Ha, H. C., Li, X.-J., Snyder, S. H., & Sawa, A. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0511316103 · Cited by 123 · see citing works
An expanded CAG repeat sequence in spinocerebellar ataxia type 7.Preprint
Lindblad, K., Savontaus, M., Stevanin, G., Holmberg, M., Digre, K., Zander, C., Ehrsson, H., David, G., Benomar, A., Nikoskelainen, E., et al. (1996) · Genome Research · doi:10.1101/gr.6.10.965 · Cited by 111 · see citing works
The Role of Glutamate Dehydrogenase in Mammalian Ammonia Metabolism
Spanaki, C., & Plaitakis, A. (2011) · Neurotoxicity Research · doi:10.1007/s12640-011-9285-4 · Cited by 108 · see citing works
Self-citationGlutamate Transport Decreases Mitochondrial pH and Modulates Oxidative Metabolism in Astrocytes
Azarias, G., Perreten, H., Lengacher, S., Poburko, D., Demaurex, N., Magistretti, P. J., & Chatton, J.-Y. (2011) · The Journal of Neuroscience · doi:10.1523/jneurosci.4378-10.2011 · Cited by 107 · see citing works
Mavrothalassitis, G., Tzimagiorgis, G., Mitsialis, S. A., Zannis, V. I., Plaitakis, A., Papamatheakis, J. D., & Moschonas, N. Κ. (1988) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.85.10.3494 · Cited by 95 · see citing works
Self-citationPlaitakis, A., Metaxari, M., & Shashidharan, P. (2000) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2000.0751862.x · Cited by 91 · see citing works
Self-citationAoki, C. J., Milner, T. A., Berger, S. B., et al. (1987) · Journal of Neuroscience Research · doi:10.1002/jnr.490180207 · Cited by 89 · see citing works
Hussain, M. M., Zannis, V. I., & Plaitakis, A. (1989) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)47124-x · Cited by 88 · see citing works
Self-citationHassel, B., & Sonnewald, U. (1995) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.1995.65052227.x · Cited by 87 · see citing works
Goodman, M., Sterner, K. N., Islam, M., Uddin, M., Sherwood, C. C., Hof, P. R., Hou, Z.-C., Lipovich, L., Jia, H., Grossman, L. I., et al. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0911239106 · Cited by 87 · see citing works
Nerve Tissue‐Specific Human Glutamate Dehydrogenase that Is Thermolabile and Highly Regulated by ADP
Shashidharan, P., Clarke, D. D., Ahmed, N., Moschonas, N. Κ., & Plaitakis, A. (1997) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.1997.68051804.x · Cited by 85 · see citing works
Self-citationTaylor, J. S., Vigneron, D. B., Murphy‐Boesch, J., et al. (1991) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.88.15.6810 · Cited by 83 · see citing works
Julliard, J. H., & Smith, E. L. (1979) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)50777-8 · Cited by 79 · see citing works
Gabriel, J. L., Zervos, P. R., & Plaut, G. W. E. (1986) · Metabolism · doi:10.1016/0026-0495(86)90175-7 · Cited by 79 · see citing works
Increased plasma concentrations of aspartate, glutamate and glycine in Parkinson's disease
Iwasaki, Y., Ikeda, K., Shiojima, T., et al. (1992) · Neuroscience Letters · doi:10.1016/0304-3940(92)90015-y · Cited by 76 · see citing works
Erecińska, M., & NELSON, D. S. (1990) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.1990.tb01967.x · Cited by 76 · see citing works
The Human Glutamate Dehydrogenase Gene Family: Gene Organization and Structural Characterization
Michaelidis, T. M., Tzimagiorgis, G., Moschonas, N. Κ., & Papamatheakis, J. D. (1993) · Genomics · doi:10.1006/geno.1993.1152 · Cited by 65 · see citing works
Rosso, L., Marques, A. C., Reichert, A. S., & Kaessmann, H. (2008) · PLoS Genetics · doi:10.1371/journal.pgen.1000150 · Cited by 65 · see citing works
Human GLUD2 Glutamate Dehydrogenase Is Expressed in Neural and Testicular Supporting Cells
Spanaki, C., Zaganas, I. V., Kleopa, K. A., et al. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.092999 · Cited by 64 · see citing works
Panten, U., Zielmann, S., Langer, J., Zünkler, B. J., & Lenzen, S. (1984) · Biochemical Journal · doi:10.1042/bj2190189 · Cited by 59 · see citing works
Quantitative ultrastructural localization of glutamate dehydrogenase in the rat cerebellar cortex
Rothe, F., Brosz, M., & Storm‐Mathisen, J. (1995) · Neuroscience · doi:10.1016/0306-4522(94)e0200-n · Cited by 59 · see citing works
Human GLUD1 and GLUD2 glutamate dehydrogenase localize to mitochondria and endoplasmic reticulum
Mastorodemos, V. C., Kotzamani, D., Zaganas, I. V., et al. (2009) · Biochemistry and Cell Biology · doi:10.1139/o09-008 · Cited by 57 · see citing works
The human GLUD2 glutamate dehydrogenase and its regulation in health and disease
Plaitakis, A., Latsoudis, H., & Spanaki, C. (2011) · Neurochemistry International · doi:10.1016/j.neuint.2011.03.015 · Cited by 56 · see citing works
Self-citationRothe, F., Schmidt, W., & Wolf, G. L. (1983) · Developmental Brain Research · doi:10.1016/0165-3806(83)90202-x · Cited by 55 · see citing works
Structural Basis for Leucine-induced Allosteric Activation of Glutamate Dehydrogenase
Tomita, T., Kuzuyama, T., & Nishiyama, M. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.260265 · Cited by 54 · see citing works
Gain-of-function variant in GLUD2 glutamate dehydrogenase modifies Parkinson's disease onset
Plaitakis, A., Latsoudis, H., Kanavouras, K., Ritz, B. R., Bronstein, J. M., Skoula, I., Mastorodemos, V. C., Papapetropoulos, S., Borompokas, N., Zaganas, I. V., et al. (2009) · European Journal of Human Genetics · doi:10.1038/ejhg.2009.179 · Cited by 54 · see citing works
Self-citationDistinct genomic signatures of adaptation in pre- and postnatal environments during human evolution
Uddin, M., Goodman, M., Erez, O., Romero, R. J., Liu, G., Islam, M., Opazo, J. C., Sherwood, C. C., Grossman, L. I., & Wildman, D. E. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0712400105 · Cited by 52 · see citing works
Intracellular pH changes produced by glutamate uptake in rat hippocampal slices
Amato, A., Ballerini, L., & Attwell, D. (1994) · Journal of Neurophysiology · doi:10.1152/jn.1994.72.4.1686 · Cited by 50 · see citing works
Zaganas, I. V., & Plaitakis, A. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m200022200 · Cited by 47 · see citing works
Self-citationZaganas, I. V., Spanaki, C., Karpusas, M., et al. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m208596200 · Cited by 45 · see citing works
Kupper, J., Ascher, P., & Neyton, J. (1998) · The Journal of Physiology · doi:10.1111/j.1469-7793.1998.001bu.x · Cited by 44 · see citing works
Kanavouras, K., Mastorodemos, V. C., Borompokas, N., et al. (2007) · Journal of Neuroscience Research · doi:10.1002/jnr.21197 · Cited by 41 · see citing works
Expression of human GLUD2 glutamate dehydrogenase in human tissues: Functional implications
Zaganas, I. V., Spanaki, C., & Plaitakis, A. (2012) · Neurochemistry International · doi:10.1016/j.neuint.2012.06.007 · Cited by 40 · see citing works
Self-citationRothe, F., Wolf, G. L., & ̈nzel, G. S. (1990) · Neuroscience · doi:10.1016/0306-4522(90)90278-c · Cited by 34 · see citing works
Regulation of glutamate dehydrogenase by Mg2+ and magnification of leucine activation by Mg2+.
Fahien, L. A., Teller, J. K., MacDonald, M. J., et al. (1990) · Molecular Pharmacology · doi:10.1016/s0026-895x(25)11054-7 · Cited by 33 · see citing works
Permeant Ion Effects on External Mg2+Block of NR1/2D NMDA Receptors
Qian, A., & Johnson, J. W. (2006) · Journal of Neuroscience · doi:10.1523/jneurosci.3453-06.2006 · Cited by 33 · see citing works
Phylogenomic evidence of adaptive evolution in the ancestry of humans
Goodman, M., & Sterner, K. N. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0914626107 · Cited by 32 · see citing works
Estrogen Modification of Human Glutamate Dehydrogenases Is Linked to Enzyme Activation State
Borompokas, N., Papachatzaki, M.-M., Kanavouras, K., Mastorodemos, V. C., Zaganas, I. V., Spanaki, C., & Plaitakis, A. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.146084 · Cited by 28 · see citing works
Self-citationComplete nucleotide sequence of human glutamate dehydrogenase cDNA
Nakatani, Y., Schneider, M., Banner, C., et al. (1988) · Nucleic Acids Research · doi:10.1093/nar/16.13.6237 · Cited by 27 · see citing works
Varki, A. P. (2004) · Nature Genetics · doi:10.1038/ng1004-1034 · Cited by 26 · see citing works
Important role of Ser443 in different thermal stability of human glutamate dehydrogenase isozymes1
Yang, S.-J., Huh, J., Hong, H., Kim, T. U., & Cho, S. (2004) · FEBS Letters · doi:10.1016/s0014-5793(04)00183-8 · Cited by 21 · see citing works
Tzimagiorgis, G., Leversha, M., Chroniary, K., et al. (1993) · Human Genetics · doi:10.1007/bf00217767 · Cited by 8 · see citing works
A marriage full of surprises; forty-five years living with glutamate dehydrogenase
Engel, P. C. (2011) · Neurochemistry International · doi:10.1016/j.neuint.2011.03.014 · Cited by 6 · see citing works
Frieden, C. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.x800003200 · Cited by 4 · see citing works
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- Authors
- Shashidharan, P., & Plaitakis, A.
- Affiliations
- Icahn School of Medicine at Mount Sinai (US)
- University of Crete (GR)
- Corresponding author
- Shashidharan, Pullanipally
- Venue
- Neurochemical Research
- Published
- 2013-12-19
- Volume
- 39
- Issue
- 3
- Pages
- 460-470
- ISSN
- 0364-3190 (ISSN-L)
- 1573-6903
- PMC
- PMC3944346
- OpenAlex
- W2073347469
- Cited by
- 43
- References
- 64
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 7 · 2023: 4 · 2022: 1 · 2021: 3 · 2020: 4 · 2019: 3 · 2018: 7 · 2017: 3 · 2016: 5 · 2015: 1 · 2014: 3
- FWCI
- 0.28
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Neurochemical Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke (NS 43038, R01NS043038)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- GluD2, glutamate dehydrogenase, GLUD1, gene duplication, human evolution, astrocytes, glutamate metabolism, excitatory neurotransmission, synaptogenesis, GTP inhibition, brain development, neurodegeneration, gain-of-function mutations
- MeSH terms
- Animals, Astrocytes, Brain, Glutamate Dehydrogenase, Humans, Mutagenesis, Site-Directed, Protein Isoforms
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