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Shuffling the Deck Anew: How NR3 Tweaks NMDA Receptor Function

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Abstract

The N-methyl-d-aspartate (NMDA) receptors are the most complex members in the family of ionotropic glutamate receptors. They are involved in long-term potentiation and underlie higher cognitive functions like memory formation and learning. On the other hand, overstimulation of NMDA receptors (NMDARs), leading to a massive influx of Ca2+ ions into the cell, is linked to neurodegenerative disorders such as for example Huntington’s disease and epilepsy. NMDARs are generally considered to be heteromeric tetramers and are conventionally thought to assemble from NR1 splice variants and NR2 subunits, which determine crucial channel properties. With the recent discovery of the functionally different NR3 subunits, many of the known features of NMDARs are being reassessed: The presence of NR3 in NMDARs decreases Mg2+ sensitivity and Ca2+ permeability and reduces agonist-induced current responses. Between altering those essential key characteristics of conventional NMDARs and forming a new class of excitatory glycine receptors when coassembling with NR1, the NR3 subunits give rise to a functionally entirely new array of “NMDA” receptors. Understanding the multifaceted influence of NR3 is imperative to further the understanding of the complex role of NMDARs in neurotransmission and higher brain functions.

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References

  1. Olney JW et al (2001) Glutamate signaling and the fetal alcohol syndrome. MRDD Res Rev 7:267–275

    CAS  Google Scholar 

  2. Goff DC, Coyle JT (2001) The emerging role of glutamate in the pathophysiology and treatment of schizophrenia. Am J Psychiatry 158:1367–1377

    Article  PubMed  CAS  Google Scholar 

  3. Duncan GE et al (2004) Deficits in sensorimotor gating and tests of social behavior in a genetic model of reduced NMDA receptor function. Behav Brain Res 153:507–519

    Article  PubMed  CAS  Google Scholar 

  4. Kleckner NW, Dingledine R (1988) Requirement for glycine in activation of NMDA-receptors expressed in Xenopus oocytes. Science 241:835–837

    Article  PubMed  CAS  Google Scholar 

  5. McBain CJ, Mayer ML (1994) N-methyl-D-aspartic acid receptor structure and function. Physiol Rev 74:723–760

    PubMed  CAS  Google Scholar 

  6. Christine CW, Choi DW (1990) Effect of zinc on NMDA receptor-mediated channel currents in cortical neurons. J Neurosci 10:108–116

    PubMed  CAS  Google Scholar 

  7. Legendre P, Westbrook GL (1990) The inhibition of single N-methyl-D-aspartate-activated channels by zinc ions on cultured rat neurones. J Physiol 429:429–449

    PubMed  CAS  Google Scholar 

  8. Hollmann M et al (1993) Zinc potentiates agonist-induced currents at certain splice variants of the NMDA receptor. Neuron 10:943–954

    Article  PubMed  CAS  Google Scholar 

  9. Kuryatov A et al (1994) Mutational analysis of the glycine-binding site of the NMDA receptor: structural similarity with bacterial amino acid-binding proteins. Neuron 12:1291–1300

    Article  PubMed  CAS  Google Scholar 

  10. Hirai H et al (1996) The glycine binding site of the N-methyl-D-aspartate receptor subunit NR1: identification of novel determinants of co-agonist potentiation in the extracellular M3-M4 loop region. Proc Natl Acad Sci U S A 93:6031–6036

    Article  PubMed  CAS  Google Scholar 

  11. Laube B et al (1997) Molecular determinants of agonist discrimination by NMDA receptor subunits: analysis of the glutamate binding site on the NR2B subunit. Neuron 18:493–503

    Article  PubMed  CAS  Google Scholar 

  12. Monyer H et al (1994) Developmental and regional expression in the rat brain and functional properties of four NMDA receptors. Neuron 12:529–540

    Article  PubMed  CAS  Google Scholar 

  13. Ciabarra AM et al (1995) Cloning and characterization of chi-1: a developmentally regulated member of a novel class of the ionotropic glutamate receptor family. J Neurosci 15:6498–6508

    PubMed  CAS  Google Scholar 

  14. Sucher NJ et al (1995) Developmental and regional expression pattern of a novel NMDA receptor-like subunit (NMDAR-L) in the rodent brain. J Neurosci 15:6509–6520

    PubMed  CAS  Google Scholar 

  15. Andersson O et al (2001) Nucleotide sequence, genomic organization, and chromosomal localization of genes encoding the human NMDA receptor subunits NR3A and NR3B. Genomics 78:178–184

    Article  PubMed  CAS  Google Scholar 

  16. Eriksson M et al (2002) Cloning and expression of the human N-methyl-D-aspartate receptor subunit NR3A. Neurosci Lett 321:177–181

    Article  PubMed  CAS  Google Scholar 

  17. Das S et al (1998) Increased NMDA current and spine density in mice lacking the NMDA receptor subunit NR3A. Nature 393:377–381

    Article  PubMed  CAS  Google Scholar 

  18. Sun L et al (1998) Identification of a long variant of mRNA encoding the NR3 subunit of the NMDA receptor: its regional distribution and developmental expression in the rat brain. FEBS Lett 441:392–396

    Article  PubMed  CAS  Google Scholar 

  19. Sasaki YF et al (2002) Characterization and comparison of the NR3A subunit of the NMDA receptor in recombinant systems and primary cortical neurons. J Neurophysiol 87:2052–2063

    PubMed  CAS  Google Scholar 

  20. Forcina MS, Ciabarra AM, Sevarino KA (1995) Cloning of chi-2: A putative member of the ionotropic glutamate receptor superfamily. Soc Neurosc (Abs) 21:438.3

    Google Scholar 

  21. Nishi M et al (2001) Motoneuron-specific expression of NR3B, a novel NMDA-type glutamate receptor subunit that works in a dominant-negative manner. J Neurosci 21:RC185

    PubMed  CAS  Google Scholar 

  22. Chatterton JE et al (2002) Excitatory glycine receptors containing the NR3 family of NMDA receptor subunits. Nature 415:793–798

    PubMed  CAS  Google Scholar 

  23. Bendel O et al (2005) Cloning and expression of the human NMDA receptor subunit NR3B in the adult human hippocampus. Neurosci Lett 377:31–36

    Article  PubMed  CAS  Google Scholar 

  24. Goebel DJ, Poosch MS (1999) NMDA receptor subunit gene expression in the rat brain: a quantitative analysis of endogenous mRNA levels of NR1Com, NR2A, NR2B, NR2C, NR2D and NR3A. Brain Res Mol Brain Res 69:164–170

    Article  PubMed  CAS  Google Scholar 

  25. Al-Hallaq RA et al (2002) Association of NR3A with the N-methyl-D-aspartate receptor NR1 and NR2 subunits. Mol Pharmacol 62:1119–1127

    Article  PubMed  CAS  Google Scholar 

  26. Wong HK et al (2002) Temporal and regional expression of NMDA receptor subunit NR3A in the mammalian brain. J Comp Neurol 450:303–317

    Article  PubMed  CAS  Google Scholar 

  27. Sucher NJ et al (2003) N-Methyl-D-Aspartate receptor subunit NR3A in the retina: Developmental expression, cellular localization, and functional aspects. Invest Ophthalmol Vis Sci 44:4451–4456

    Article  PubMed  Google Scholar 

  28. Henson MA et al (2008) Developmental Regulation of the NMDA Receptor Subunits, NR3A and NR1, in Human Prefrontal Cortex. Cereb Cortex (in press) (Feb 28)

  29. Nilsson A et al (2007) Analysis of NR3A receptor subunits in human native NMDA receptors. Brain Res 1186:102–112

    Article  PubMed  CAS  Google Scholar 

  30. Mueller HT, Meador-Woodruff JH (2005) Distribution of the NMDA receptor NR3A subunit in the adult pig-tail macaque brain. J Chem Neuroanat 29:157–172

    Article  PubMed  CAS  Google Scholar 

  31. Fukaya M, Hayashi Y, Watanabe M (2005) NR2 to NR3B subunit switchover of NMDA receptors in early postnatal motoneurons. Eur J Neurosci 21:1432–1436

    Article  PubMed  Google Scholar 

  32. Wee KS-L et al (2008) Immunolocalization of NMDA receptor subunit NR3B in selected structures in the rat forebrain, cerebellum, and lumbar spinal cord. J Comp Neurol 509:118–135

    Article  PubMed  CAS  Google Scholar 

  33. Perez-Otano I et al (2001) Assembly with the NR1 subunit is required for surface expression of NR3A-containing NMDA receptors. J Neurosci 21:1228–1237

    PubMed  CAS  Google Scholar 

  34. Matsuda K et al (2003) Specific assembly with the NMDA receptor 3B subunit controls surface expression and calcium permeability of NMDA receptors. J Neurosci 23:10064–10073

    PubMed  CAS  Google Scholar 

  35. Atlason PT et al (2007) N-Methyl-D-aspartate (NMDA) receptor subunit NR1 forms the substrate for oligomeric assembly of the NMDA receptor. J Biol Chem 282:25299–25307

    Article  PubMed  CAS  Google Scholar 

  36. Schuler T et al (2008) Formation of NR1/NR2 and NR1/NR3 heterodimers constitutes the initial step in N-methyl-D-aspartate receptor assembly. J Biol Chem 283:37–46

    Article  PubMed  Google Scholar 

  37. Okabe S, Miwa A, Okado H (1999) Alternative splicing of the C-terminal domain regulates cell surface expression of the NMDA receptor NR1 subunit. J Neurosci 19:7781–7792

    PubMed  CAS  Google Scholar 

  38. Standley S et al (2000) PDZ domain suppression of an ER retention signal in NMDA receptor NR1 splice variants. Neuron 28:887–898

    Article  PubMed  CAS  Google Scholar 

  39. Scott DB et al (2001) An NMDA receptor ER retention signal regulated by phosphorylation and alternative splicing. J Neurosci 21:3063–3072

    PubMed  CAS  Google Scholar 

  40. Ulbrich MH, Isacoff EY (2007) Subunit counting in membrane-bound proteins. Nat Methods 4:319–321

    PubMed  CAS  Google Scholar 

  41. Karadottir R et al (2005) NMDA receptors are expressed in oligodendrocytes and activated in ischaemia. Nature 438:1162–1166

    Article  PubMed  CAS  Google Scholar 

  42. Tong G et al (2008) Modulation of NMDA receptor properties and synaptic transmission by the NR3A subunit in mouse hippocampal and cerebrocortical neurons. J Neurophysiol 99:122–132

    Article  PubMed  CAS  Google Scholar 

  43. Perez-Otano I et al (2006) Endocytosis and synaptic removal of NR3A-containing NMDA receptors by PACSIN1/syndapin1. Nat Neurosci 9:611–621

    Article  PubMed  CAS  Google Scholar 

  44. Matsuda K et al (2002) Cloning and characterization of a novel NMDA receptor subunit NR3B: a dominant subunit that reduces calcium permeability. Brain Res Mol Brain Res 100:43–52

    Article  PubMed  CAS  Google Scholar 

  45. Villmann C et al (1999) Investigation by ion channel domain transplantation of rat glutamate receptor subunits, orphan receptors and a putative NMDA receptor subunit. Eur J Neurosci 11:1765–1778

    Article  PubMed  CAS  Google Scholar 

  46. Wada A et al (2006) NR3A modulates the outer vestibule of the “NMDA” receptor channel. J Neurosci 26:13156–13166

    Article  PubMed  CAS  Google Scholar 

  47. Smothers CT, Woodward JJ (2007) Pharmacological characterization of glycine-activated currents in HEK 293 cells expressing N-methyl-D-aspartate NR1 and NR3 subunits. J Pharmacol Exp Ther 322:739–748

    Article  PubMed  CAS  Google Scholar 

  48. Piña-Crespo JC, Heinemann SF (2004) Physiological and pharmacological properties of recombinant NR3-type receptors expressed in mammalian cells. Program No. 957.1. 2004 Abstract Viewer/Itinerary Planner. Society for Neuroscience, Washington, DC

    Google Scholar 

  49. Sobolevsky AI, Yelshansky MV, Wollmuth LP (2004) The outer pore of the glutamate receptor channel has 2-fold rotational symmetry. Neuron 41:367–378

    Article  PubMed  CAS  Google Scholar 

  50. Yamakura T et al (2005) The NR3B subunit does not alter the anesthetic sensitivities of recombinant N-methyl-D-aspartate receptors. Anesth Analg 100:1687–1692

    Article  PubMed  CAS  Google Scholar 

  51. Yao Y, Mayer ML (2006) Characterization of a soluble ligand binding domain of the NMDA receptor regulatory subunit NR3A. J Neurosci 26:4559–4566

    Article  PubMed  CAS  Google Scholar 

  52. Madry C et al (2007) Principal role of NR3 subunits in NR1/NR3 excitatory glycine receptor function. Biochem Biophys Res Commun 354:102–108

    Article  PubMed  CAS  Google Scholar 

  53. Awobuluyi M et al (2007) Subunit-specific roles of glycine-binding domains in activation of NR1/NR3 N-methyl-D-aspartate receptors. Mol Pharmacol 71:112–122

    Article  PubMed  CAS  Google Scholar 

  54. Smothers CT, Woodward JJ (2003) Effect of the NR3 subunit on ethanol inhibition of recombinant NMDA receptors. Brain Res 987:117–121

    Article  PubMed  CAS  Google Scholar 

  55. Niemann S et al (2008) Motoneuron-specific NR3B gene: no association with ALS and evidence for a common null allele. Neurology 70:666–676

    Article  PubMed  CAS  Google Scholar 

  56. Niemann S et al (2007) Genetic ablation of NMDA receptor subunit NR3B in mouse reveals motoneuronal and nonmotoneuronal phenotypes. Eur J Neurosci 26:1407–1420

    Article  PubMed  Google Scholar 

  57. Chan SF, Sucher NJ (2001) An NMDA receptor signaling complex with protein phosphatase 2A. J Neurosci 21:7985–7992

    PubMed  CAS  Google Scholar 

  58. Ma OK, Sucher NJ (2004) Molecular interaction of NMDA receptor subunit NR3A with protein phosphatase 2A. Neuroreport 15:1447–1450

    Article  PubMed  CAS  Google Scholar 

  59. Emamian ES, Karayiorgou M, Gogos JA (2004) Decreased phosphorylation of NMDA receptor type 1 at serine 897 in brains of patients with schizophrenia. J Neurosci 24:1561–1564

    Article  PubMed  CAS  Google Scholar 

  60. Brody SA et al (2005) A developmental influence of the N-methyl-D-aspartate receptor NR3A subunit on prepulse inhibition of startle. Biol Psychiatry 57:1147–1152

    Article  PubMed  CAS  Google Scholar 

  61. Mueller HT, Meador-Woodruff JH (2004) NR3A NMDA receptor subunit mRNA expression in schizophrenia, depression and bipolar disorder. Schizophr Res 71:361–370

    Article  PubMed  Google Scholar 

  62. Salter MG, Fern R (2005) NMDA receptors are expressed in developing oligodendrocyte processes and mediate injury. Nature 438:1167–1171

    Article  PubMed  CAS  Google Scholar 

  63. Micu I et al (2006) NMDA receptors mediate calcium accumulation in myelin during chemical ischaemia. Nature 439:988–992

    PubMed  CAS  Google Scholar 

  64. Verkhratsky A, Kirchhoff F (2007) NMDA Receptors in glia. Neuroscientist 13:28–37

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

We thank Sabine M. Schmid and Elke Muth-Köhne for critical reading of this manuscript.

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Authors and Affiliations

  1. International Graduate School of Neuroscience (IGSN), Ruhr University Bochum, Bochum, Germany

    Nora A. Cavara

  2. Ruhr-University Research School, Ruhr University Bochum, Bochum, Germany

    Nora A. Cavara

  3. Department of Biochemistry I–Receptor Biochemistry, Ruhr University Bochum, Building NC Room 6/171, Universitätsstr. 150, 44780, Bochum, Germany

    Nora A. Cavara & Michael Hollmann

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  1. Nora A. Cavara
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  2. Michael Hollmann
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Correspondence to Michael Hollmann.

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Cavara, N.A., Hollmann, M. Shuffling the Deck Anew: How NR3 Tweaks NMDA Receptor Function. Mol Neurobiol 38, 16–26 (2008). https://doi.org/10.1007/s12035-008-8029-9

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