Molecular pharmacology of human NMDA receptors

Maiken Hedegaard; Kasper Bø Hansen; Karen Toftegaard Andersen; Hans Bräuner-Osborne; Stephen F Traynelis

doi:10.1016/j.neuint.2011.11.016

Molecular pharmacology of human NMDA receptors

Maiken Hedegaard, Kasper Bø Hansen, Karen Toftegaard Andersen, Hans Bräuner-Osborne, Stephen F Traynelis

50 Citations (Scopus)

Abstract

N-methyl-d-aspartate (NMDA) receptors are ionotropic glutamate receptors that mediate excitatory neurotransmission. NMDA receptors are also important drug targets that are implicated in a number of pathophysiological conditions. To facilitate the transition from lead compounds in pre-clinical animal models to drug candidates for human use, it is important to establish whether NMDA receptor ligands have similar properties at rodent and human NMDA receptors. Here, we compare amino acid sequences for human and rat NMDA receptor subunits and discuss inter-species variation in the context of our current knowledge of the relationship between NMDA receptor structure and function. We summarize studies on the biophysical properties of human NMDA receptors and compare these properties to those of rat orthologs. Finally, we provide a comprehensive pharmacological characterization that allows side-by-side comparison of agonists, un-competitive antagonists, GluN2B-selective non-competitive antagonists, and GluN2C/D-selective modulators at recombinant human and rat NMDA receptors. The evaluation of biophysical properties and pharmacological probes acting at different sites on the receptor suggest that the binding sites and conformational changes leading to channel gating in response to agonist binding are highly conserved between human and rat NMDA receptors. In summary, the results of this study suggest that no major detectable differences exist in the pharmacological and functional properties of human and rat NMDA receptors.

Original language	English
Journal	Neurochemistry International
Volume	61
Issue number	4
Pages (from-to)	601-609
ISSN	0197-0186
DOIs	https://doi.org/10.1016/j.neuint.2011.11.016
Publication status	Published - Sept 2012

Access to Document

10.1016/j.neuint.2011.11.016

Cite this

@article{8dcf26d30abf4a029d86784b9675aea4,

title = "Molecular pharmacology of human NMDA receptors",

abstract = "N-methyl-d-aspartate (NMDA) receptors are ionotropic glutamate receptors that mediate excitatory neurotransmission. NMDA receptors are also important drug targets that are implicated in a number of pathophysiological conditions. To facilitate the transition from lead compounds in pre-clinical animal models to drug candidates for human use, it is important to establish whether NMDA receptor ligands have similar properties at rodent and human NMDA receptors. Here, we compare amino acid sequences for human and rat NMDA receptor subunits and discuss inter-species variation in the context of our current knowledge of the relationship between NMDA receptor structure and function. We summarize studies on the biophysical properties of human NMDA receptors and compare these properties to those of rat orthologs. Finally, we provide a comprehensive pharmacological characterization that allows side-by-side comparison of agonists, un-competitive antagonists, GluN2B-selective non-competitive antagonists, and GluN2C/D-selective modulators at recombinant human and rat NMDA receptors. The evaluation of biophysical properties and pharmacological probes acting at different sites on the receptor suggest that the binding sites and conformational changes leading to channel gating in response to agonist binding are highly conserved between human and rat NMDA receptors. In summary, the results of this study suggest that no major detectable differences exist in the pharmacological and functional properties of human and rat NMDA receptors.",

author = "Maiken Hedegaard and Hansen, {Kasper B{\o}} and Andersen, {Karen Toftegaard} and Hans Br{\"a}uner-Osborne and Traynelis, {Stephen F}",

note = "Keywords: Ionotropic glutamate receptor; NMDA; Pharmacology; Electrophysiology; Structure–function",

year = "2012",

month = sep,

doi = "10.1016/j.neuint.2011.11.016",

language = "English",

volume = "61",

pages = "601--609",

journal = "Neurochemistry International",

issn = "0197-0186",

publisher = "Elsevier",

number = "4",

}

TY - JOUR

T1 - Molecular pharmacology of human NMDA receptors

AU - Hedegaard, Maiken

AU - Hansen, Kasper Bø

AU - Andersen, Karen Toftegaard

AU - Bräuner-Osborne, Hans

AU - Traynelis, Stephen F

N1 - Keywords: Ionotropic glutamate receptor; NMDA; Pharmacology; Electrophysiology; Structure–function

PY - 2012/9

Y1 - 2012/9

N2 - N-methyl-d-aspartate (NMDA) receptors are ionotropic glutamate receptors that mediate excitatory neurotransmission. NMDA receptors are also important drug targets that are implicated in a number of pathophysiological conditions. To facilitate the transition from lead compounds in pre-clinical animal models to drug candidates for human use, it is important to establish whether NMDA receptor ligands have similar properties at rodent and human NMDA receptors. Here, we compare amino acid sequences for human and rat NMDA receptor subunits and discuss inter-species variation in the context of our current knowledge of the relationship between NMDA receptor structure and function. We summarize studies on the biophysical properties of human NMDA receptors and compare these properties to those of rat orthologs. Finally, we provide a comprehensive pharmacological characterization that allows side-by-side comparison of agonists, un-competitive antagonists, GluN2B-selective non-competitive antagonists, and GluN2C/D-selective modulators at recombinant human and rat NMDA receptors. The evaluation of biophysical properties and pharmacological probes acting at different sites on the receptor suggest that the binding sites and conformational changes leading to channel gating in response to agonist binding are highly conserved between human and rat NMDA receptors. In summary, the results of this study suggest that no major detectable differences exist in the pharmacological and functional properties of human and rat NMDA receptors.

AB - N-methyl-d-aspartate (NMDA) receptors are ionotropic glutamate receptors that mediate excitatory neurotransmission. NMDA receptors are also important drug targets that are implicated in a number of pathophysiological conditions. To facilitate the transition from lead compounds in pre-clinical animal models to drug candidates for human use, it is important to establish whether NMDA receptor ligands have similar properties at rodent and human NMDA receptors. Here, we compare amino acid sequences for human and rat NMDA receptor subunits and discuss inter-species variation in the context of our current knowledge of the relationship between NMDA receptor structure and function. We summarize studies on the biophysical properties of human NMDA receptors and compare these properties to those of rat orthologs. Finally, we provide a comprehensive pharmacological characterization that allows side-by-side comparison of agonists, un-competitive antagonists, GluN2B-selective non-competitive antagonists, and GluN2C/D-selective modulators at recombinant human and rat NMDA receptors. The evaluation of biophysical properties and pharmacological probes acting at different sites on the receptor suggest that the binding sites and conformational changes leading to channel gating in response to agonist binding are highly conserved between human and rat NMDA receptors. In summary, the results of this study suggest that no major detectable differences exist in the pharmacological and functional properties of human and rat NMDA receptors.

U2 - 10.1016/j.neuint.2011.11.016

DO - 10.1016/j.neuint.2011.11.016

M3 - Journal article

C2 - 22197913

SN - 0197-0186

VL - 61

SP - 601

EP - 609

JO - Neurochemistry International

JF - Neurochemistry International

IS - 4

ER -

Molecular pharmacology of human NMDA receptors

Abstract

Access to Document

Fingerprint

Cite this