Subunit-specific agonist activity at NR2A-, NR2B-, NR2C-, and NR2D-containing N-methyl-D-aspartate glutamate receptors

Kevin Erreger; Matthew T. Geballe; Anders Skov Kristensen; Philip E. Chen; Kasper Bø Hansen; C. Justin Lee; Hongjie Yuan; Phuong Le; Polina N. Lyuboslavsky; Nicola Micale; Lars Jørgensen; Rasmus Prætorius Clausen; David J. A. Wyllie; James P. Snyder; Stephen F. Traynelis

doi:10.1124/mol.107.037333

Subunit-specific agonist activity at NR2A-, NR2B-, NR2C-, and NR2D-containing N-methyl-D-aspartate glutamate receptors

Kevin Erreger, Matthew T. Geballe, Anders Skov Kristensen, Philip E. Chen, Kasper Bø Hansen, C. Justin Lee, Hongjie Yuan, Phuong Le, Polina N. Lyuboslavsky, Nicola Micale, Lars Jørgensen, Rasmus Prætorius Clausen, David J. A. Wyllie, James P. Snyder, Stephen F. Traynelis

112 Citations (Scopus)

Abstract

The four N-methyl-d-aspartate (NMDA) receptor NR2 subunits (NR2A-D) have different developmental, anatomical, and functional profiles that allow them to serve different roles in normal and neuropathological situations. Identification of subunit-selective NMDA receptor agonists, antagonists, or modulators could prove to be both valuable pharmacological tools as well as potential new therapeutic agents. We evaluated the potency and efficacy of a wide range of glutamate-like compounds at NR1/NR2A, NR1/NR2B, NR1/NR2C, and NR1/NR2D receptors. Twenty-five of 53 compounds examined exhibited agonist activity at the glutamate binding site of NMDA receptors. Concentration-response relationships were determined for these agonists at each NR2 subunit. We find consistently higher potency at the NR2D subunit for a wide range of dissimilar structures, with (2S,4R)-4-methylglutamate (SYM2081) showing the greatest differential potency between NR2A- and NR2D-containing receptors (46-fold). Analysis of chimeric NR2A/D receptors suggests that enhanced agonist potency for NR2D is controlled by residues in both of the domains (Domain1 and Domain2) that compose the bilobed agonist binding domain. Molecular dynamics (MD) simulations comparing a crystallography-based hydrated NR1/NR2A model with a homology-based NR1/NR2D hydrated model of the agonist binding domains suggest that glutamate exhibits a different binding mode in NR2D compared with NR2A that accommodates a 4-methyl substitution in SYM2081. Mutagenesis of functionally divergent residues supports the conclusions drawn based on the modeling studies. Despite high homology and conserved atomic contact residues within the agonist binding pocket of NR2A and NR2D, glutamate adopts a different binding orientation that could be exploited for the development of subunit selective agonists and competitive antagonists.

Original language	English
Journal	Molecular Pharmacology
Volume	72
Issue number	4
Pages (from-to)	907-920
ISSN	0026-895X
DOIs	https://doi.org/10.1124/mol.107.037333
Publication status	Published - 2007

Keywords

Former Faculty of Pharmaceutical Sciences

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10.1124/mol.107.037333

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Erreger, K., Geballe, M. T., Kristensen, A. S., Chen, P. E., Hansen, K. B., Lee, C. J., Yuan, H., Le, P., Lyuboslavsky, P. N., Micale, N., Jørgensen, L., Clausen, R. P., Wyllie, D. J. A., Snyder, J. P., & Traynelis, S. F. (2007). Subunit-specific agonist activity at NR2A-, NR2B-, NR2C-, and NR2D-containing N-methyl-D-aspartate glutamate receptors. Molecular Pharmacology, 72(4), 907-920. https://doi.org/10.1124/mol.107.037333

Erreger, K, Geballe, MT, Kristensen, AS, Chen, PE, Hansen, KB, Lee, CJ, Yuan, H, Le, P, Lyuboslavsky, PN, Micale, N, Jørgensen, L, Clausen, RP, Wyllie, DJA, Snyder, JP & Traynelis, SF 2007, 'Subunit-specific agonist activity at NR2A-, NR2B-, NR2C-, and NR2D-containing N-methyl-D-aspartate glutamate receptors', Molecular Pharmacology, vol. 72, no. 4, pp. 907-920. https://doi.org/10.1124/mol.107.037333

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title = "Subunit-specific agonist activity at NR2A-, NR2B-, NR2C-, and NR2D-containing N-methyl-D-aspartate glutamate receptors",

abstract = "The four N-methyl-d-aspartate (NMDA) receptor NR2 subunits (NR2A-D) have different developmental, anatomical, and functional profiles that allow them to serve different roles in normal and neuropathological situations. Identification of subunit-selective NMDA receptor agonists, antagonists, or modulators could prove to be both valuable pharmacological tools as well as potential new therapeutic agents. We evaluated the potency and efficacy of a wide range of glutamate-like compounds at NR1/NR2A, NR1/NR2B, NR1/NR2C, and NR1/NR2D receptors. Twenty-five of 53 compounds examined exhibited agonist activity at the glutamate binding site of NMDA receptors. Concentration-response relationships were determined for these agonists at each NR2 subunit. We find consistently higher potency at the NR2D subunit for a wide range of dissimilar structures, with (2S,4R)-4-methylglutamate (SYM2081) showing the greatest differential potency between NR2A- and NR2D-containing receptors (46-fold). Analysis of chimeric NR2A/D receptors suggests that enhanced agonist potency for NR2D is controlled by residues in both of the domains (Domain1 and Domain2) that compose the bilobed agonist binding domain. Molecular dynamics (MD) simulations comparing a crystallography-based hydrated NR1/NR2A model with a homology-based NR1/NR2D hydrated model of the agonist binding domains suggest that glutamate exhibits a different binding mode in NR2D compared with NR2A that accommodates a 4-methyl substitution in SYM2081. Mutagenesis of functionally divergent residues supports the conclusions drawn based on the modeling studies. Despite high homology and conserved atomic contact residues within the agonist binding pocket of NR2A and NR2D, glutamate adopts a different binding orientation that could be exploited for the development of subunit selective agonists and competitive antagonists.",

keywords = "Former Faculty of Pharmaceutical Sciences",

author = "Kevin Erreger and Geballe, {Matthew T.} and Kristensen, {Anders Skov} and Chen, {Philip E.} and Hansen, {Kasper B{\o}} and Lee, {C. Justin} and Hongjie Yuan and Phuong Le and Lyuboslavsky, {Polina N.} and Nicola Micale and Lars J{\o}rgensen and Clausen, {Rasmus Pr{\ae}torius} and Wyllie, {David J. A.} and Snyder, {James P.} and Traynelis, {Stephen F.}",

note = "Keywords: Animals; Binding Sites; Crystallography, X-Ray; Dose-Response Relationship, Drug; Excitatory Amino Acid Agonists; Models, Molecular; Mutagenesis, Site-Directed; Patch-Clamp Techniques; Protein Conformation; Rats; Receptors, N-Methyl-D-Aspartate; Recombinant Proteins; Xenopus laevis",

year = "2007",

doi = "10.1124/mol.107.037333",

language = "English",

volume = "72",

pages = "907--920",

journal = "Molecular Pharmacology",

issn = "0026-895X",

publisher = "American Society for Pharmacology and Experimental Therapeutics",

number = "4",

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TY - JOUR

T1 - Subunit-specific agonist activity at NR2A-, NR2B-, NR2C-, and NR2D-containing N-methyl-D-aspartate glutamate receptors

AU - Erreger, Kevin

AU - Geballe, Matthew T.

AU - Kristensen, Anders Skov

AU - Chen, Philip E.

AU - Hansen, Kasper Bø

AU - Lee, C. Justin

AU - Yuan, Hongjie

AU - Le, Phuong

AU - Lyuboslavsky, Polina N.

AU - Micale, Nicola

AU - Jørgensen, Lars

AU - Clausen, Rasmus Prætorius

AU - Wyllie, David J. A.

AU - Snyder, James P.

AU - Traynelis, Stephen F.

N1 - Keywords: Animals; Binding Sites; Crystallography, X-Ray; Dose-Response Relationship, Drug; Excitatory Amino Acid Agonists; Models, Molecular; Mutagenesis, Site-Directed; Patch-Clamp Techniques; Protein Conformation; Rats; Receptors, N-Methyl-D-Aspartate; Recombinant Proteins; Xenopus laevis

PY - 2007

Y1 - 2007

N2 - The four N-methyl-d-aspartate (NMDA) receptor NR2 subunits (NR2A-D) have different developmental, anatomical, and functional profiles that allow them to serve different roles in normal and neuropathological situations. Identification of subunit-selective NMDA receptor agonists, antagonists, or modulators could prove to be both valuable pharmacological tools as well as potential new therapeutic agents. We evaluated the potency and efficacy of a wide range of glutamate-like compounds at NR1/NR2A, NR1/NR2B, NR1/NR2C, and NR1/NR2D receptors. Twenty-five of 53 compounds examined exhibited agonist activity at the glutamate binding site of NMDA receptors. Concentration-response relationships were determined for these agonists at each NR2 subunit. We find consistently higher potency at the NR2D subunit for a wide range of dissimilar structures, with (2S,4R)-4-methylglutamate (SYM2081) showing the greatest differential potency between NR2A- and NR2D-containing receptors (46-fold). Analysis of chimeric NR2A/D receptors suggests that enhanced agonist potency for NR2D is controlled by residues in both of the domains (Domain1 and Domain2) that compose the bilobed agonist binding domain. Molecular dynamics (MD) simulations comparing a crystallography-based hydrated NR1/NR2A model with a homology-based NR1/NR2D hydrated model of the agonist binding domains suggest that glutamate exhibits a different binding mode in NR2D compared with NR2A that accommodates a 4-methyl substitution in SYM2081. Mutagenesis of functionally divergent residues supports the conclusions drawn based on the modeling studies. Despite high homology and conserved atomic contact residues within the agonist binding pocket of NR2A and NR2D, glutamate adopts a different binding orientation that could be exploited for the development of subunit selective agonists and competitive antagonists.

AB - The four N-methyl-d-aspartate (NMDA) receptor NR2 subunits (NR2A-D) have different developmental, anatomical, and functional profiles that allow them to serve different roles in normal and neuropathological situations. Identification of subunit-selective NMDA receptor agonists, antagonists, or modulators could prove to be both valuable pharmacological tools as well as potential new therapeutic agents. We evaluated the potency and efficacy of a wide range of glutamate-like compounds at NR1/NR2A, NR1/NR2B, NR1/NR2C, and NR1/NR2D receptors. Twenty-five of 53 compounds examined exhibited agonist activity at the glutamate binding site of NMDA receptors. Concentration-response relationships were determined for these agonists at each NR2 subunit. We find consistently higher potency at the NR2D subunit for a wide range of dissimilar structures, with (2S,4R)-4-methylglutamate (SYM2081) showing the greatest differential potency between NR2A- and NR2D-containing receptors (46-fold). Analysis of chimeric NR2A/D receptors suggests that enhanced agonist potency for NR2D is controlled by residues in both of the domains (Domain1 and Domain2) that compose the bilobed agonist binding domain. Molecular dynamics (MD) simulations comparing a crystallography-based hydrated NR1/NR2A model with a homology-based NR1/NR2D hydrated model of the agonist binding domains suggest that glutamate exhibits a different binding mode in NR2D compared with NR2A that accommodates a 4-methyl substitution in SYM2081. Mutagenesis of functionally divergent residues supports the conclusions drawn based on the modeling studies. Despite high homology and conserved atomic contact residues within the agonist binding pocket of NR2A and NR2D, glutamate adopts a different binding orientation that could be exploited for the development of subunit selective agonists and competitive antagonists.

KW - Former Faculty of Pharmaceutical Sciences

U2 - 10.1124/mol.107.037333

DO - 10.1124/mol.107.037333

M3 - Journal article

C2 - 17622578

SN - 0026-895X

VL - 72

SP - 907

EP - 920

JO - Molecular Pharmacology

JF - Molecular Pharmacology

IS - 4

ER -

Subunit-specific agonist activity at NR2A-, NR2B-, NR2C-, and NR2D-containing N-methyl-D-aspartate glutamate receptors

Abstract

Keywords

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