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Title: Regulation of NMDAR activation efficiency by environmental factors and subunit composition

Journal Article · · Journal of General Physiology

NMDA receptors (NMDAR) convert the major excitatory neurotransmitter glutamate into a synaptic signal. A key question is how efficiently the ion channel opens in response to the rapid exposure to presynaptic glutamate release. Here, we applied glutamate to single channel outside-out patches and measured the successes of channel openings and the latency to first opening to assay the activation efficiency of NMDARs under different physiological conditions and with different human subunit compositions. For GluN1/GluN2A receptors, we find that various factors, including intracellular ATP and GTP, can enhance the efficiency of activation presumably via the intracellular C-terminal domain. Notably, an energy-based internal solution or increasing the time between applications to increase recovery time improved efficiency. However, even under these optimized conditions and with a 1-s glutamate application, there remained around 10–15% inefficiency. Channel activation became more inefficient with brief synaptic-like pulses of glutamate at 2 ms. Of the different NMDAR subunit compositions, GluN2B-containing NMDARs showed the lowest success rate and longest latency to first openings, highlighting that they display the most distinct activation mechanism. In contrast, putative triheteromeric GluN1/GluN2A/GluN2B receptors showed high activation efficiency. Despite the low open probability, NMDARs containing either GluN2C or GluN2D subunits displayed high activation efficiency, nearly comparable with that for GluN2A-containing receptors. These results highlight that activation efficiency in NMDARs can be regulated by environmental surroundings and varies across different subunits.

Sponsoring Organization:
USDOE
OSTI ID:
2478564
Journal Information:
Journal of General Physiology, Journal Name: Journal of General Physiology Journal Issue: 1 Vol. 157; ISSN 0022-1295
Publisher:
Rockefeller University PressCopyright Statement
Country of Publication:
United States
Language:
English

References (79)

Schizophrenia: Basic and Clinical book January 2017
Rundown of NMDA-receptor mediated currents is resistant to lowering intracellular [Ca2+] and is prevented by ATP in rat spinal dorsal horn neurons journal July 1993
Successive openings of the same acetylcholine receptor channel are correlated in open time journal April 1983
Calcineurin acts via the C-terminus of NR2A to modulate desensitization of NMDA receptors journal April 2002
Allosteric Changes in the NMDA Receptor Associated with Calcium-Dependent Inactivation journal December 2020
Slow AMPA receptors in hippocampal principal cells journal August 2021
Subtype-specific conformational landscape of NMDA receptor gating journal August 2024
Mechanisms of NMDA receptor regulation journal December 2023
De novo mutations and rare variants occurring in NMDA receptors journal April 2018
Structural insights into assembly and function of GluN1-2C, GluN1-2A-2C, and GluN1-2D NMDARs journal December 2022
Distinct Functional and Pharmacological Properties of Triheteromeric GluN1/GluN2A/GluN2B NMDA Receptors journal March 2014
Allosteric Interactions between NMDA Receptor Subunits Shape the Developmental Shift in Channel Properties journal April 2017
Triheteromeric GluN1/GluN2A/GluN2C NMDARs with Unique Single-Channel Properties Are the Dominant Receptor Population in Cerebellar Granule Cells journal July 2018
NMDA Receptors Require Multiple Pre-opening Gating Steps for Efficient Synaptic Activity journal February 2021
Gating mechanism and a modulatory niche of human GluN1-GluN2A NMDA receptors journal August 2021
Modal gating of GluN1/GluN2D NMDA receptors journal August 2013
The diverse and complex modes of action of anti-NMDA receptor autoantibodies journal August 2021
Conformational Analysis of NMDA Receptor GluN1, GluN2, and GluN3 Ligand-Binding Domains Reveals Subtype-Specific Characteristics journal October 2013
Glutamate and Glycine Binding to the NMDA Receptor journal July 2018
Synaptic calcium transients in single spines indicate that NMDA receptors are not saturated journal May 1999
A reinterpretation of mammalian sodium channel gating based on single channel recording journal December 1983
Channel kinetics determine the time course of NMDA receptor-mediated synaptic currents journal August 1990
Changing subunit composition of heteromeric NMDA receptors during development of rat cortex journal March 1994
Regulation of NMDA receptors by tyrosine kinases and phosphatases journal May 1994
Reaction mechanism determines NMDA receptor response to repetitive stimulation journal August 2004
NMDA receptor structures reveal subunit arrangement and pore architecture journal June 2014
Ligand-specific deactivation time course of GluN1/GluN2D NMDA receptors journal April 2011
Multiple pore conformations driven by asynchronous movements of voltage sensors in a eukaryotic sodium channel journal January 2013
Mechanical coupling maintains the fidelity of NMDA receptor–mediated currents journal May 2014
Activation of NR1/NR2B NMDA receptors journal January 2003
Modal gating of NMDA receptors and the shape of their synaptic response journal April 2003
NMDA receptor subunit diversity: impact on receptor properties, synaptic plasticity and disease journal May 2013
A conserved glycine harboring disease-associated mutations permits NMDA receptor slow deactivation and high Ca2+ permeability journal September 2018
Conformational rearrangement of the NMDA receptor amino-terminal domain during activation and allosteric modulation journal May 2021
GluN2A and GluN2B NMDA receptors use distinct allosteric routes journal August 2021
Autoantibodies in neurological disease journal May 2021
Molecular mechanism of ligand gating and opening of NMDA receptor journal July 2024
Distinct structure and gating mechanism in diverse NMDA receptors with GluN2C and GluN2D subunits journal March 2023
The glutamate story journal January 2006
Ca(2+)-independent reduction of N-methyl-D-aspartate channel activity by protein tyrosine phosphatase. journal February 1996
Triheteromeric NR1/NR2A/NR2B Receptors Constitute the Major N -Methyl-d-aspartate Receptor Population in Adult Hippocampal Synapses journal December 2010
Modulating the Intrinsic Disorder in the Cytoplasmic Domain Alters the Biological Activity of the N-Methyl-d-aspartate-sensitive Glutamate Receptor journal August 2013
Conformational Selection and Submillisecond Dynamics of the Ligand-binding Domain of the N-Methyl-d-aspartate Receptor journal July 2016
Extracellular Ca2+ ions reduce NMDA receptor conductance and gating journal October 2014
Divergent roles of a peripheral transmembrane segment in AMPA and NMDA receptors journal May 2017
Efficiency measures the conversion of agonist binding energy into receptor conformational change journal January 2019
NMDA receptor channel gating control by the pre-M1 helix journal March 2020
Neuronal Correlates of Local, Lateral, and Translaminar Inhibition with Reference to Cortical Columns journal October 2008
Slow excitatory synaptic currents generated by AMPA receptors journal October 2021
Pharmacological properties and H+ sensitivity of excitatory amino acid receptor channels in rat cerebellar granule neurones. journal February 1991
Rundown of N‐methyl‐D‐aspartate channels during whole‐cell recording in rat hippocampal neurons: role of Ca2+ and ATP. journal October 1993
Subunit-specific gating controls rat NR1/NR2A and NR1/NR2B NMDA channel kinetics and synaptic signalling profiles: NMDA receptor gating journal February 2005
Subunit-specific mechanisms and proton sensitivity of NMDA receptor channel block: Proton sensitivity of NMDA receptor channel blockers journal May 2007
Activation of recombinant NR1/NR2C NMDA receptors journal September 2008
GluN1 splice variant control of GluN1/GluN2D NMDA receptors journal June 2012
Molecular bases of NMDA receptor subtype-dependent properties: Molecular bases of NMDA receptor subtype-dependent properties journal September 2014
Cholesterol modulates open probability and desensitization of NMDA receptors journal March 2015
Structure, Function, and Pharmacology of Glutamate Receptor Ion Channels journal October 2021
Glutamate Receptor Ion Channels: Structure, Regulation, and Function journal August 2010
Crystal structure of a heterotetrameric NMDA receptor ion channel journal May 2014
The time course of glutamate in the synaptic cleft journal November 1992
Long-Term Potentiation: From CaMKII to AMPA Receptor Trafficking journal February 2016
Input-specific maturation of NMDAR-mediated transmission onto parvalbumin-expressing interneurons in layers 2/3 of the visual cortex journal December 2018
Molecular Mechanism of Disease-Associated Mutations in the Pre-M1 Helix of NMDA Receptors and Potential Rescue Pharmacology journal January 2017
Block of AMPA Receptor Desensitization by a Point Mutation outside the Ligand-Binding Domain journal May 2004
Triheteromeric NMDA Receptors at Hippocampal Synapses journal May 2013
Inactivation of NMDA channels in cultured hippocampal neurons by intracellular calcium journal February 1993
Synaptic NMDA receptor channels have a low open probability journal April 1995
Subtype-Dependence of NMDA Receptor Channel Open Probability journal August 1999
Palmitoylation Controls NMDA Receptor Function and Steroid Sensitivity journal February 2021
A Molecular Determinant of Subtype-Specific Desensitization in Ionotropic Glutamate Receptors journal March 2016
Target-Specific Regulation of Synaptic Amplitudes in the Neocortex journal January 2005
Phosphorylation of Ser1166 on GluN2B by PKA Is Critical to Synaptic NMDA Receptor Function and Ca2+Signaling in Spines journal January 2014
Specific Sites within the Ligand-Binding Domain and Ion Channel Linkers Modulate NMDA Receptor Gating journal September 2010
Asynchronous Movements Prior to Pore Opening in NMDA Receptors journal July 2013
Excitotoxicity: Still Hammering the Ischemic Brain in 2020 journal October 2020
Molecular Mechanisms of Glutamate Toxicity in Parkinson’s Disease journal November 2020
Excitatory and inhibitory D-serine binding to the NMDA receptor journal October 2022
Agonist efficiency links binding and gating in a nicotinic receptor journal July 2023

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