title: Modulation of NMDA receptor properties and synaptic transmission by the NR3A subunit in mouse hippocampal and cerebrocortical neurons.
abstract: Expression of the NR3A subunit with NR1/NR2 in Xenopus oocytes or mammalian cell lines leads to a reduction in N-methyl-d-aspartate (NMDA)-induced currents and decreased Mg(2+) sensitivity and Ca(2+) permeability compared with NR1/NR2 receptors. Consistent with these findings, neurons from NR3A knockout (KO) mice exhibit enhanced NMDA-induced currents. Recombinant NR3A can also form excitatory glycine receptors with NR1 in the absence of NR2. However, the effects of NR3A on channel properties in neurons and synaptic transmission have not been fully elucidated. To study physiological roles of NR3A subunits, we generated NR3A transgenic (Tg) mice. Cultured NR3A Tg neurons exhibited two populations of NMDA receptor (NMDAR) channels, reduced Mg(2+) sensitivity, and decreased Ca(2+) permeability in response to NMDA/glycine, but glycine alone did not elicit excitatory currents. In addition, NMDAR-mediated excitatory postsynaptic currents (EPSCs) in NR3A Tg hippocampal slices showed reduced Mg(2+) sensitivity, consistent with the notion that NR3A subunits incorporated into synaptic NMDARs. To study the function of endogenous NR3A subunits, we compared NMDAR-mediated EPSCs in NR3A KO and WT control mice. In NR3A KO mice, the ratio of the amplitudes of the NMDAR-mediated component to alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor-mediated component of the EPSC was significantly larger than that seen in WT littermates. This result suggests that NR3A subunits contributed to the NMDAR-mediated component of the EPSC in WT mice. Taken together, these results show that NR3A subunits contribute to NMDAR responses from both synaptic and extrasynaptic receptors, likely composed of NR1, NR2, and NR3 subunits.
authors.affiliation: Center for Neuroscience, Aging, and Stem Cell Research, Burnham Institute for Medical Research, La Jolla, California 92037, USA. gtong@burnham.org
authors.forename: Gary
authors.initials: G
authors.lastname: Tong
authors.forename: Hiroto
authors.initials: H
authors.lastname: Takahashi
authors.forename: Shichun
authors.initials: S
authors.lastname: Tu
authors.forename: Yeonsook
authors.initials: Y
authors.lastname: Shin
authors.forename: Maria
authors.initials: M
authors.lastname: Talantova
authors.forename: Wagner
authors.initials: W
authors.lastname: Zago
authors.forename: Peng
authors.initials: P
authors.lastname: Xia
authors.forename: Zhiguo
authors.initials: Z
authors.lastname: Nie
authors.forename: Thomas
authors.initials: T
authors.lastname: Goetz
authors.forename: Dongxian
authors.initials: D
authors.lastname: Zhang
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Lipton
authors.forename: Nobuki
authors.initials: N
authors.lastname: Nakanishi
mesh_terms: D000818:Animals; D002118:Calcium / Q000494:pharmacology; D020013:Calcium Signaling / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000378:metabolism*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism*; D015640:Ion Channel Gating / Q000235:genetics; D008274:Magnesium / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism*; D009924:Organ Culture Techniques; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics; D009435:Synaptic Transmission / Q000187:drug effects / Q000235:genetics*; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology
chemical_list: C409466:NR1 NMDA receptor; C120997:NR2A NMDA receptor; C464437:NR3A NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D011993:Recombinant Fusion Proteins; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D008274:Magnesium; D002118:Calcium