Abstract
In the presence of glutamate and co-agonists, e.g., glycine, the N-methyl-D-aspartate receptor (NMDAR) plays an important role in physiological and pathophysiological brain processes. Previous studies indicate glycine could inhibit NMDAR responses induced by high concentration of NMDA in hippocampal neurons. The mechanism underlying this inhibitory impact, however, has been unclear. In this study, the whole-cell patch-clamp recording and Ca2+ imaging with Fluo-3/AM under laser scanning confocal microscope were used to analyze the possible involvement of NMDAR subunits in this effect. We found that the peak current of NMDARs and Ca2+ influx induced by high concentration of NMDA were reduced by treatment of glycine (0.03–10 μmol L−1) in a dose-dependent manner, and that the glycine-dependent inhibition of NMDAR responses, which were induced at 300 μmol L−1 NMDA, was reversed by ZnCl2 through the blocking of the NR2A subunit of NMDARs, but was less influenced by ifenprodil, a NR2B inhibitor. Our results suggest that the glycine-dependent inactivation of NMDARs is potentially modulated by the regulatory subunit NR2A.
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Li F, Tsien J Z. Memory and the NMDA receptors. N Engl J Med, 2009, 361: 302–303
Paoletti P, Neyton J. NMDA receptor subunits: function and pharmacology. Curr Opin Pharmacol, 2007, 7: 39–47
Kartvelishvily E, Shleper M, Balan L, et al. Neuron-derived D-serine release provides a novel means to activate N-methyl-D-aspartate receptors. J Biol Chem, 2006, 281: 14151–14162
Kleckner N W, Dingledine R. Requirement for glycine in activation of NMDA-receptors expressed in Xenopus oocytes. Science, 1988, 241: 835–837
Dingledine R, Borges K, Bowie D, et al. The glutamate receptor ion channels. Pharmacol Rev, 1999, 51: 7–61
Nahum-Levy R, Lipinski D, Shavit S, et al. Desensitization of NMDA receptor channels is modulated by glutamate agonists. Biophys J, 2001, 80: 2152–2166
Krupp J J, Vissel B, Heinemann S F, et al. Calcium-dependent inactivation of recombinant N-methyl-D-aspartate receptors is NR2 subunit specific. Mol Pharmacol, 1996, 50: 1680–1688
Krupp J J, Vissel B, Thomas C G, et al. Interactions of calmodulin and alpha-actinin with the NR1 subunit modulate Ca2+-dependent inactivation of NMDA receptors. J Neurosci, 1999, 19: 1165–1178
Legendre P, Rosenmund C, Westbrook G L. Inactivation of NMDA channels in cultured hippocampal neurons by intracellular calcium. J Neurosci, 1993, 13: 674–684
Nong Y, Huang Y Q, Ju W, et al. Glycine binding primes NMDA receptor internalization. Nature, 2003, 422: 302–307
Krupp J J, Vissel B, Heinemann S F, et al. N-terminal domains in the NR2 subunit control desensitization of NMDA receptors. Neuron, 1998, 20: 317–327
Benveniste M, Clements J, Vyklicky L, et al. A kinetic analysis of the modulation of N-methyl-D-aspartic acid receptors by glycine in mouse cultured hippocampal neurones. J Physiol, 1990, 428: 333–357
Zhang Y F, Li X, Peng L L, et al. Novel glycine-dependent inactivation of NMDA receptors in cultured hippocampal neurons. Neurosci Bull, 2012, 28: 550–560
Liu L, Wong T P, Pozza M F, et al. Role of NMDA receptor subtypes in governing the direction of hippocampal synaptic plasticity. Science, 2004, 304: 1021–1024
Massey P V, Johnson B E, Moult P R, et al. Differential roles of NR2A and NR2B-containing NMDA receptors in cortical long-term potentiation and long-term depression. J Neurosci, 2004, 24: 7821–7828
Kaech S, Banker G. Culturing hippocampal neurons. Nat Protoc, 2006, 1: 2406–2415
Vyklicky L. Calcium-mediated modulation of N-methyl-D-aspartate (NMDA) responses in cultured rat hippocampal neurones. J Physiol, 1993, 470: 575–600
Rosenmund C, Feltz A, Westbrook G L. Synaptic NMDA receptor channels have a low open probability. J Neurosci, 1995, 15: 2788–2795
Rosenmund C, Feltz A, Westbrook G L. Calcium-dependent inactivation of synaptic NMDA receptors in hippocampal neurons. J Neurophysiol, 1995, 73: 427–430
Monyer H, Sprengel R, Schoepfer R, et al. Heteromeric NMDA receptors: molecular and functional distinction of subtypes. Science, 1992, 256: 1217–1221
Vicini S, Wang J F, Li J H, et al. Functional and pharmacological differences between recombinant N-methyl-D-aspartate receptors. J Neurophysiol, 1998, 79: 555–566
Kendrick S J, Dichter M A, Wilcox K S. Characterization of desensitization in recombinant N-methyl-D-aspartate receptors: comparison with native receptors in cultured hippocampal neurons. Brain Res Mol Brain Res, 1998, 57: 10–20
Paoletti P, Ascher P, Neyton J. High-affinity zinc inhibition of NMDA NR1-NR2A receptors. J Neurosci, 1997, 17: 5711–5725
Hatton C J, Paoletti P. Modulation of triheteromeric NMDA receptors by N-terminal domain ligands. Neuron, 2005, 46: 261–274
Gielen M, Le Goff A, Stroebel D, et al. Structural rearrangements of NR1/NR2A NMDA receptors during allosteric inhibition. Neuron, 2008, 57: 80–93
Erreger K, Geballe M T, Dravid S M, et al. Mechanism of partial agonism at NMDA receptors for a conformationally restricted glutamate analog. J Neurosci, 2005, 25: 7858–7866
Martina M, Gorfinkel Y, Halman S, et al. Glycine transporter type 1 blockade changes NMDA receptor-mediated responses and LTP in hippocampal CA1 pyramidal cells by altering extracellular glycine levels. J Physiol, 2004, 557: 489–500
Petrovic M, Horak M, Sedlacek M, et al. Physiology and pathology of NMDA receptors. Prague Med Rep, 2005, 106: 113–136
Gardoni F, Polli F, Cattabeni F, et al. Calcium-calmodulin-dependent protein kinase II phosphorylation modulates PSD-95 binding to NMDA receptors. Eur J Neurosci, 2006, 24: 2694–2704
Rao V R, Finkbeiner S. NMDA and AMPA receptors: old channels, new tricks. Trends Neurosci, 2007, 30: 284–291
Takeda A, Fuke S, Ando M, et al. Positive modulation of long-term potentiation at hippocampal CA1 synapses by low micromolar concentrations of zinc. Neuroscience, 2009, 158: 585–591
Takeda A, Iwaki H, Ando M, et al. Zinc differentially acts on components of long-term potentiation at hippocampal CA1 synapses. Brain Res, 2010, 1323: 59–64
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Li, X., Chen, Z., Jiang, Z. et al. Zinc reverses glycine-dependent inactivation of NMDARs in cultured rat hippocampal neurons. Sci. China Life Sci. 55, 1075–1081 (2012). https://doi.org/10.1007/s11427-012-4421-9
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DOI: https://doi.org/10.1007/s11427-012-4421-9