Molecular Basis for Subtype Specificity and High-Affinity Zinc Inhibition in the GluN1-GluN2A NMDA Receptor Amino-Terminal Domain

Romero-Hernandez, Annabel; Simorowski, Noriko; Karakas, Erkan; Furukawa, Hiro

doi:10.1016/j.neuron.2016.11.006

Molecular Basis for Subtype Specificity and High-Affinity Zinc Inhibition in the GluN1-GluN2A NMDA Receptor Amino-Terminal Domain

Journal Article · Thu Dec 01 00:00:00 EST 2016 · Neuron

DOI:https://doi.org/10.1016/j.neuron.2016.11.006· OSTI ID:1352282

Romero-Hernandez, Annabel ^[1]; Simorowski, Noriko ^[1]; Karakas, Erkan ^[1]; Furukawa, Hiro ^[1]

Cold Spring Harbor Laboratory Cold Spring Harbor, NY (United States)

Zinc is vastly present in the mammalian brain and controls functions of various cell surface receptors to regulate neurotransmission. A distinctive characteristic of N-methyl-D-aspartate (NMDA) receptors containing a GluN2A subunit is that their ion channel activity is allosterically inhibited by a nano-molar concentration of zinc that binds to an extracellular domain called an amino-terminal domain (ATD). Despite physiological importance, the molecular mechanism underlying the high-affinity zinc inhibition has been incomplete because of the lack of a GluN2A ATD structure. Here we show the first crystal structures of the heterodimeric GluN1-GluN2A ATD, which provide the complete map of the high-affinity zinc-binding site and reveal distinctive features from the ATD of the GluN1-GluN2B subtype. Perturbation of hydrogen bond networks at the hinge of the GluN2A bi-lobe structure affects both zinc inhibition and open probability, supporting the general model in which the bi-lobe motion in ATD regulates the channel activity in NMDA receptors.

View Accepted Manuscript (DOE)

Research Organization:: Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)

Sponsoring Organization:: USDOE Office of Science (SC)

OSTI ID:: 1352282

Journal Information:: Neuron, Journal Name: Neuron Journal Issue: 6 Vol. 92; ISSN 0896-6273

Publisher:: Cell Press - ElsevierCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

References (41)

Enhancing the secretion of recombinant proteins by engineering N-glycosylation sites Liu, Yan; Nguyen, Anton; Wolfert, Robert L. Biotechnology Progress, Vol. 25, Issue 5 https://doi.org/10.1002/btpr.241	journal	July 2009
A Trafficking Checkpoint Controls GABAB Receptor Heterodimerization Margeta-Mitrovic, Marta; Jan, Yuh Nung; Jan, Lily Yeh Neuron, Vol. 27, Issue 1 https://doi.org/10.1016/S0896-6273(00)00012-X	journal	July 2000
Molecular Organization of a Zinc Binding N-Terminal Modulatory Domain in a NMDA Receptor Subunit Paoletti, Pierre; Perin-Dureau, Florent; Fayyazuddin, Amir Neuron, Vol. 28, Issue 3 https://doi.org/10.1016/S0896-6273(00)00163-X	journal	December 2000
Identification and Mechanism of Action of Two Histidine Residues Underlying High-Affinity Zn2+ Inhibition of the NMDA Receptor Choi, Yun-Beom; Lipton, Stuart A. Neuron, Vol. 23, Issue 1 https://doi.org/10.1016/S0896-6273(00)80763-1	journal	May 1999
Four Residues of the Extracellular N-Terminal Domain of the NR2A Subunit Control High-Affinity Zn2+ Binding to NMDA Receptors Fayyazuddin, Amir; Villarroel, Alvaro; Le Goff, Anne Neuron, Vol. 25, Issue 3 https://doi.org/10.1016/S0896-6273(00)81070-3	journal	March 2000
The Actions of Synaptically Released Zinc at Hippocampal Mossy Fiber Synapses Vogt, Kaspar; Mellor, Jack; Tong, Gang Neuron, Vol. 26, Issue 1 https://doi.org/10.1016/S0896-6273(00)81149-6	journal	April 2000
Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies Dalmau, Josep; Gleichman, Amy J.; Hughes, Ethan G. The Lancet Neurology, Vol. 7, Issue 12 https://doi.org/10.1016/S1474-4422(08)70224-2	journal	December 2008
Mechanism of NMDA Receptor Inhibition and Activation Zhu, Shujia; Stein, Richard A.; Yoshioka, Craig Cell, Vol. 165, Issue 3 https://doi.org/10.1016/j.cell.2016.03.028	journal	April 2016
Structural Rearrangements of NR1/NR2A NMDA Receptors during Allosteric Inhibition Gielen, Marc; Le Goff, Anne; Stroebel, David Neuron, Vol. 57, Issue 1 https://doi.org/10.1016/j.neuron.2007.11.021	journal	January 2008
Structural Insights into Competitive Antagonism in NMDA Receptors Jespersen, Annie; Tajima, Nami; Fernandez-Cuervo, Gabriela Neuron, Vol. 81, Issue 2 https://doi.org/10.1016/j.neuron.2013.11.033	journal	January 2014
Zinc Dynamics and Action at Excitatory Synapses Vergnano, Angela Maria; Rebola, Nelson; Savtchenko, Leonid P. Neuron, Vol. 82, Issue 5 https://doi.org/10.1016/j.neuron.2014.04.034	journal	June 2014
Positive Allosteric Modulators of GluN2A-Containing NMDARs with Distinct Modes of Action and Impacts on Circuit Function Hackos, David H.; Lupardus, Patrick J.; Grand, Teddy Neuron, Vol. 89, Issue 5 https://doi.org/10.1016/j.neuron.2016.01.016	journal	March 2016
Functional evidence for a twisted conformation of the NMDA receptor GluN2A subunit N-terminal domain Stroebel, David; Carvalho, Stéphanie; Paoletti, Pierre Neuropharmacology, Vol. 60, Issue 1 https://doi.org/10.1016/j.neuropharm.2010.07.003	journal	January 2011
Altered zinc sensitivity of NMDA receptors harboring clinically-relevant mutations Serraz, Benjamin; Grand, Teddy; Paoletti, Pierre Neuropharmacology, Vol. 109 https://doi.org/10.1016/j.neuropharm.2016.06.008	journal	October 2016
A structural biology perspective on NMDA receptor pharmacology and function Regan, Michael C.; Romero-Hernandez, Annabel; Furukawa, Hiro Current Opinion in Structural Biology, Vol. 33 https://doi.org/10.1016/j.sbi.2015.07.012	journal	August 2015
Discovery of GluN2A-Selective NMDA Receptor Positive Allosteric Modulators (PAMs): Tuning Deactivation Kinetics via Structure-Based Design Volgraf, Matthew; Sellers, Benjamin D.; Jiang, Yu Journal of Medicinal Chemistry, Vol. 59, Issue 6 https://doi.org/10.1021/acs.jmedchem.5b02010	journal	March 2016
Micromolar concentrations of Zn2+ antagonize NMDA and GABA responses of hippocampal neurons Westbrook, Gary L.; Mayer, Mark L. Nature, Vol. 328, Issue 6131 https://doi.org/10.1038/328640a0	journal	August 1987
Structure of the zinc-bound amino-terminal domain of the NMDA receptor NR2B subunit Karakas, Erkan; Simorowski, Noriko; Furukawa, Hiro The EMBO Journal, Vol. 28, Issue 24 https://doi.org/10.1038/emboj.2009.338	journal	November 2009
Molecular basis of positive allosteric modulation of GluN2B NMDA receptors by polyamines Mony, Laetitia; Zhu, Shujia; Carvalho, Stéphanie The EMBO Journal, Vol. 30, Issue 15 https://doi.org/10.1038/emboj.2011.203	journal	June 2011
Subunit arrangement and function in NMDA receptors Furukawa, Hiroyasu; Singh, Satinder K.; Mancusso, Romina Nature, Vol. 438, Issue 7065 https://doi.org/10.1038/nature04089	journal	November 2005
Mechanism of differential control of NMDA receptor activity by NR2 subunits Gielen, Marc; Retchless, Beth Siegler; Mony, Laetitia Nature, Vol. 459, Issue 7247 https://doi.org/10.1038/nature07993	journal	April 2009
Subunit arrangement and phenylethanolamine binding in GluN1/GluN2B NMDA receptors Karakas, Erkan; Simorowski, Noriko; Furukawa, Hiro Nature, Vol. 475, Issue 7355 https://doi.org/10.1038/nature10180	journal	June 2011
NMDA receptor structures reveal subunit arrangement and pore architecture Lee, Chia-Hsueh; Lü, Wei; Michel, Jennifer Carlisle Nature, Vol. 511, Issue 7508 https://doi.org/10.1038/nature13548	journal	June 2014
Activation of NMDA receptors and the mechanism of inhibition by ifenprodil Tajima, Nami; Karakas, Erkan; Grant, Timothy Nature, Vol. 534, Issue 7605 https://doi.org/10.1038/nature17679	journal	May 2016
Zinc alleviates pain through high-affinity binding to the NMDA receptor NR2A subunit Nozaki, Chihiro; Vergnano, Angela Maria; Filliol, Dominique Nature Neuroscience, Vol. 14, Issue 8 https://doi.org/10.1038/nn.2844	journal	July 2011
Allosteric interaction between the amino terminal domain and the ligand binding domain of NR2A Zheng, F.; Erreger, K.; Low, C. -M. Nature Neuroscience, Vol. 4, Issue 9 https://doi.org/10.1038/nn0901-894	journal	August 2001
Molecular determinants of coordinated proton and zinc inhibition of N-methyl-D-aspartate NR1/NR2A receptors Low, C. -M.; Zheng, F.; Lyuboslavsky, P. Proceedings of the National Academy of Sciences, Vol. 97, Issue 20 https://doi.org/10.1073/pnas.180307497	journal	September 2000
An Endoplasmic Reticulum Retention Signal Located in the Extracellular Amino-terminal Domain of the NR2A Subunit of N-Methyl-d-aspartate Receptors Qiu, Shuang; Zhang, Xiao-min; Cao, Jing-yuan Journal of Biological Chemistry, Vol. 284, Issue 30 https://doi.org/10.1074/jbc.M109.004960	journal	July 2009
Amino-terminal Domain Tetramer Organization and Structural Effects of Zinc Binding in the N-Methyl-d-aspartate (NMDA) Receptor Sirrieh, Rita E.; MacLean, David M.; Jayaraman, Vasanthi Journal of Biological Chemistry, Vol. 288, Issue 31 https://doi.org/10.1074/jbc.M113.482356	journal	August 2013
The Serine Protease Plasmin Cleaves the Amino-terminal Domain of the NR2A Subunit to Relieve Zinc Inhibition of the N-Methyl-d-aspartate Receptors Yuan, Hongjie; Vance, Katie M.; Junge, Candice E. Journal of Biological Chemistry, Vol. 284, Issue 19 https://doi.org/10.1074/jbc.M805123200	journal	May 2009
Structural Determinants of Agonist Efficacy at the Glutamate Binding Site of N -Methyl-d-Aspartate Receptors Hansen, Kasper B.; Tajima, Nami; Risgaard, Rune Molecular Pharmacology, Vol. 84, Issue 1 https://doi.org/10.1124/mol.113.085803	journal	April 2013
Differential Sensitivity of Recombinant N -Methyl-d-Aspartate Receptor Subtypes to Zinc Inhibition Chen, Nansheng; Moshaver, Ali; Raymond, Lynn A. Molecular Pharmacology, Vol. 51, Issue 6 https://doi.org/10.1124/mol.51.6.1015	journal	June 1997
Glutamate Receptor Ion Channels: Structure, Regulation, and Function Traynelis, Stephen F.; Wollmuth, Lonnie P.; McBain, Chris J. Pharmacological Reviews, Vol. 62, Issue 3 https://doi.org/10.1124/pr.109.002451	journal	August 2010
Crystal structure of a heterotetrameric NMDA receptor ion channel Karakas, E.; Furukawa, H. Science, Vol. 344, Issue 6187 https://doi.org/10.1126/science.1251915	journal	May 2014
KVFinder: steered identification of protein cavities as a PyMOL plugin Oliveira, Saulo HP; Ferraz, Felipe AN; Honorato, Rodrigo V. BMC Bioinformatics, Vol. 15, Issue 1 https://doi.org/10.1186/1471-2105-15-197	journal	January 2014
Control of NMDA Receptor Function by the NR2 Subunit Amino-Terminal Domain Yuan, H.; Hansen, K. B.; Vance, K. M. Journal of Neuroscience, Vol. 29, Issue 39 https://doi.org/10.1523/JNEUROSCI.1365-09.2009	journal	September 2009
High-Affinity Zinc Inhibition of NMDA NR1–NR2A Receptors Paoletti, Pierre; Ascher, Philippe; Neyton, Jacques The Journal of Neuroscience, Vol. 17, Issue 15 https://doi.org/10.1523/JNEUROSCI.17-15-05711.1997	journal	August 1997
Control of Voltage-Independent Zinc Inhibition of NMDA Receptors by the NR1 Subunit Traynelis, Stephen F.; Burgess, Michele F.; Zheng, Fang The Journal of Neuroscience, Vol. 18, Issue 16 https://doi.org/10.1523/JNEUROSCI.18-16-06163.1998	journal	August 1998
C-Terminal Interaction Is Essential for Surface Trafficking But Not for Heteromeric Assembly of GABA _B Receptors Pagano, Adriana; Rovelli, Giorgio; Mosbacher, Johannes The Journal of Neuroscience, Vol. 21, Issue 4 https://doi.org/10.1523/JNEUROSCI.21-04-01189.2001	journal	February 2001
The NMDA Receptor M3 Segment Is a Conserved Transduction Element Coupling Ligand Binding to Channel Opening Jones, Kevin S.; VanDongen, Hendrika M. A.; VanDongen, Antonius M. J. The Journal of Neuroscience, Vol. 22, Issue 6 https://doi.org/10.1523/JNEUROSCI.22-06-02044.2002	journal	March 2002
The Micromolar Zinc-Binding Domain on the NMDA Receptor Subunit NR2B Rachline, J. Journal of Neuroscience, Vol. 25, Issue 2 https://doi.org/10.1523/JNEUROSCI.3967-04.2005	journal	January 2005

Cited By (16)

Lupus autoantibodies act as positive allosteric modulators at GluN2A-containing NMDA receptors and impair spatial memory Chan, Kelvin; Nestor, Jacquelyn; Huerta, Tomás S. Nature Communications, Vol. 11, Issue 1 https://doi.org/10.1038/s41467-020-15224-w	journal	March 2020
A NMDA-receptor calcium influx assay sensitive to stimulation by glutamate and glycine/D-serine Guo, Hongqiu; Camargo, L. Miguel; Yeboah, Fred Scientific Reports, Vol. 7, Issue 1 https://doi.org/10.1038/s41598-017-11947-x	journal	September 2017
Structure, function, and allosteric modulation of NMDA receptors Hansen, Kasper B.; Yi, Feng; Perszyk, Riley E. Journal of General Physiology, Vol. 150, Issue 8 https://doi.org/10.1085/jgp.201812032	journal	July 2018
Zinc mediates the neuronal activity–dependent anti-apoptotic effect Qiu, Mei; Shentu, Yang-ping; Zeng, Ji PLOS ONE, Vol. 12, Issue 8 https://doi.org/10.1371/journal.pone.0182150	journal	August 2017
Marine Mammals’ NMDA Receptor Structure: Possible Adaptation to High Pressure Environment Bliznyuk, Alice; Golan, Hava; Grossman, Yoram Frontiers in Physiology, Vol. 9 https://doi.org/10.3389/fphys.2018.01633	journal	November 2018
Zinc in Cellular Regulation: The Nature and Significance of “Zinc Signals” Maret, Wolfgang International Journal of Molecular Sciences, Vol. 18, Issue 11 https://doi.org/10.3390/ijms18112285	journal	October 2017
Plasma Membrane Na+-Coupled Citrate Transporter (SLC13A5) and Neonatal Epileptic Encephalopathy Bhutia, Yangzom; Kopel, Jonathan; Lawrence, John Molecules, Vol. 22, Issue 3 https://doi.org/10.3390/molecules22030378	journal	February 2017
Recent progress in allosteric modulators for GluN2A subunit and development of GluN2A-selective nuclear imaging probes He, Yingfang; Mu, Linjing; Ametamey, Simon M. Journal of Labelled Compounds and Radiopharmaceuticals, Vol. 62, Issue 8 https://doi.org/10.1002/jlcr.3744	journal	June 2019
Removal of the Fe( iii ) site promotes activation of the human cystic fibrosis transmembrane conductance regulator by high-affinity Zn( ii ) binding Wang, Guangyu Metallomics, Vol. 10, Issue 2 https://doi.org/10.1039/c7mt00315c	journal	January 2018
High affinity interactions of Pb ²⁺ with synaptotagmin I Katti, Sachin; Her, Bin; Srivastava, Atul K. Metallomics, Vol. 10, Issue 9 https://doi.org/10.1039/c8mt00135a	journal	January 2018
Dissociated hippocampal neurons exhibit distinct Zn²⁺ dynamics in a stimulation method-dependent manner Sanford, Lynn; Palmer, Amy E. https://doi.org/10.1101/2020.01.03.894501	posted_content	January 2020
High affinity interactions of Pb²⁺ with Synaptotagmin I Katti, Sachin; Her, Bin; Srivastava, Atul K. https://doi.org/10.1101/348748	posted_content	June 2018
Lupus auto-antibodies act as positive allosteric modulators at NMDA receptors and induce spatial memory deficits Chan, Kelvin; Nestor, Jacquelyn; Huerta, Tomás S. https://doi.org/10.1101/791715	posted_content	October 2019
Properties of Triheteromeric N -Methyl-d-Aspartate Receptors Containing Two Distinct GluN1 Isoforms Yi, Feng; Zachariassen, Linda G.; Dorsett, Katherine N. Molecular Pharmacology, Vol. 93, Issue 5 https://doi.org/10.1124/mol.117.111427	journal	February 2018
Cryo-EM structures of the triheteromeric NMDA receptor and its allosteric modulation Lü, Wei; Du, Juan; Goehring, April Science, Vol. 355, Issue 6331 https://doi.org/10.1126/science.aal3729	journal	February 2017
An inter‐dimer allosteric switch controls NMDA receptor activity Esmenjaud, Jean‐Baptiste; Stroebel, David; Chan, Kelvin The EMBO Journal, Vol. 38, Issue 2 https://doi.org/10.15252/embj.201899894	journal	November 2018

Similar Records

Activation of NMDA receptors and the mechanism of inhibition by ifenprodil

Journal Article · Sun May 01 20:00:00 EDT 2016 · Nature (London) · OSTI ID:1352281

Structural basis of subunit selectivity for competitive NMDA receptor antagonists with preference for GluN2A over GluN2B subunits

Journal Article · Sun Jul 30 20:00:00 EDT 2017 · Proceedings of the National Academy of Sciences of the United States of America · OSTI ID:1400292

Structure of the Zinc-Bound Amino-Terminal Domain of the NMDA Receptor NR2B Subunit

Journal Article · Wed Dec 31 23:00:00 EST 2008 · EMBO Journal · OSTI ID:1019750

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
N-methyl-D-aspartate receptors
amino-terminal domain
crystal structure
ifenprodil
ionotropic glutamate receptors
subtype specificity
zinc inhibition

Molecular Basis for Subtype Specificity and High-Affinity Zinc Inhibition in the GluN1-GluN2A NMDA Receptor Amino-Terminal Domain

Citation Formats

References (41)

Cited By (16)

Similar Records

Related Subjects