Distinct functional and pharmacological properties of triheteromeric GluN1/GluN2A/GluN2B NMDA receptors

Kasper B. Hansen; Kevin K. Ogden; Hongjie Yuan; Stephen F. Traynelis

doi:10.1016/j.neuron.2014.01.035

Distinct functional and pharmacological properties of triheteromeric GluN1/GluN2A/GluN2B NMDA receptors

Kasper B. Hansen
, Kevin K. Ogden
, Hongjie Yuan
, Stephen F. Traynelis

Division of Biological and Biomedical Sciences

Emory University

Research output: Contribution to journal › Article › peer-review

260 Scopus citations

Abstract

NMDA receptors are tetrameric ligand-gated ion channels comprised of GluN1, GluN2, and GluN3 subunits. Two different GluN2 subunits have been identified in most NMDA receptor-expressing cells, and the majority of native receptors are triheteromers containing two GluN1 and two different GluN2. In contrast to diheteromeric NMDA receptors, little is known about the function of triheteromers. We developed a method to provide selective cell-surface expression of recombinant GluN1/GluN2A/GluN2B triheteromers and compared properties of these receptors with those of GluN1/GluN2A and GluN1/GluN2B diheteromers. We show that glutamate deactivation of triheteromers is distinct from those of GluN1/GluN2A and GluN1/GluN2B and reveal modulation of triheteromers by subunit-selective antagonists ifenprodil, CP-101,606, TCN-201, and extracellular Zn²⁺. Furthermore, kinetic measurements suggest variation in the ifenprodil binding site of triheteromers compared to GluN1/GluN2B diheteromers. This work provides insight into the distinct properties of GluN1/GluN2A/GluN2B triheteromers, which are presumably the most abundant NMDA receptors in the adult forebrain.

Original language	English
Pages (from-to)	1084-1096
Number of pages	13
Journal	Neuron
Volume	81
Issue number	5
DOIs	https://doi.org/10.1016/j.neuron.2014.01.035
State	Published - Mar 5 2014

Funding

The authors thank A. Tankovic, J. Zhang, and P. Le for excellent technical assistance and T. Nakagawa for helpful discussions. This work was supported by the National Institutes of Health-National Institute of Neurological Disorders and Stroke (NS036654), the Villum Kann Rasmussen Foundation, and the Lundbeck Foundation. Stephen F. Traynelis is a cofounder of NeurOp, Inc., a pharmaceutical company that is developing NMDA receptor modulators for clinical use.

Funder number
R01NS036654

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10.1016/j.neuron.2014.01.035

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title = "Distinct functional and pharmacological properties of triheteromeric GluN1/GluN2A/GluN2B NMDA receptors",

abstract = "NMDA receptors are tetrameric ligand-gated ion channels comprised of GluN1, GluN2, and GluN3 subunits. Two different GluN2 subunits have been identified in most NMDA receptor-expressing cells, and the majority of native receptors are triheteromers containing two GluN1 and two different GluN2. In contrast to diheteromeric NMDA receptors, little is known about the function of triheteromers. We developed a method to provide selective cell-surface expression of recombinant GluN1/GluN2A/GluN2B triheteromers and compared properties of these receptors with those of GluN1/GluN2A and GluN1/GluN2B diheteromers. We show that glutamate deactivation of triheteromers is distinct from those of GluN1/GluN2A and GluN1/GluN2B and reveal modulation of triheteromers by subunit-selective antagonists ifenprodil, CP-101,606, TCN-201, and extracellular Zn2+. Furthermore, kinetic measurements suggest variation in the ifenprodil binding site of triheteromers compared to GluN1/GluN2B diheteromers. This work provides insight into the distinct properties of GluN1/GluN2A/GluN2B triheteromers, which are presumably the most abundant NMDA receptors in the adult forebrain.",

author = "Hansen, \{Kasper B.\} and Ogden, \{Kevin K.\} and Hongjie Yuan and Traynelis, \{Stephen F.\}",

note = "Funding Information: The authors thank A. Tankovic, J. Zhang, and P. Le for excellent technical assistance and T. Nakagawa for helpful discussions. This work was supported by the National Institutes of Health-National Institute of Neurological Disorders and Stroke (NS036654), the Villum Kann Rasmussen Foundation, and the Lundbeck Foundation. Stephen F. Traynelis is a cofounder of NeurOp, Inc., a pharmaceutical company that is developing NMDA receptor modulators for clinical use. ",

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AU - Yuan, Hongjie

AU - Traynelis, Stephen F.

N1 - Funding Information: The authors thank A. Tankovic, J. Zhang, and P. Le for excellent technical assistance and T. Nakagawa for helpful discussions. This work was supported by the National Institutes of Health-National Institute of Neurological Disorders and Stroke (NS036654), the Villum Kann Rasmussen Foundation, and the Lundbeck Foundation. Stephen F. Traynelis is a cofounder of NeurOp, Inc., a pharmaceutical company that is developing NMDA receptor modulators for clinical use.

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N2 - NMDA receptors are tetrameric ligand-gated ion channels comprised of GluN1, GluN2, and GluN3 subunits. Two different GluN2 subunits have been identified in most NMDA receptor-expressing cells, and the majority of native receptors are triheteromers containing two GluN1 and two different GluN2. In contrast to diheteromeric NMDA receptors, little is known about the function of triheteromers. We developed a method to provide selective cell-surface expression of recombinant GluN1/GluN2A/GluN2B triheteromers and compared properties of these receptors with those of GluN1/GluN2A and GluN1/GluN2B diheteromers. We show that glutamate deactivation of triheteromers is distinct from those of GluN1/GluN2A and GluN1/GluN2B and reveal modulation of triheteromers by subunit-selective antagonists ifenprodil, CP-101,606, TCN-201, and extracellular Zn2+. Furthermore, kinetic measurements suggest variation in the ifenprodil binding site of triheteromers compared to GluN1/GluN2B diheteromers. This work provides insight into the distinct properties of GluN1/GluN2A/GluN2B triheteromers, which are presumably the most abundant NMDA receptors in the adult forebrain.

AB - NMDA receptors are tetrameric ligand-gated ion channels comprised of GluN1, GluN2, and GluN3 subunits. Two different GluN2 subunits have been identified in most NMDA receptor-expressing cells, and the majority of native receptors are triheteromers containing two GluN1 and two different GluN2. In contrast to diheteromeric NMDA receptors, little is known about the function of triheteromers. We developed a method to provide selective cell-surface expression of recombinant GluN1/GluN2A/GluN2B triheteromers and compared properties of these receptors with those of GluN1/GluN2A and GluN1/GluN2B diheteromers. We show that glutamate deactivation of triheteromers is distinct from those of GluN1/GluN2A and GluN1/GluN2B and reveal modulation of triheteromers by subunit-selective antagonists ifenprodil, CP-101,606, TCN-201, and extracellular Zn2+. Furthermore, kinetic measurements suggest variation in the ifenprodil binding site of triheteromers compared to GluN1/GluN2B diheteromers. This work provides insight into the distinct properties of GluN1/GluN2A/GluN2B triheteromers, which are presumably the most abundant NMDA receptors in the adult forebrain.

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Distinct functional and pharmacological properties of triheteromeric GluN1/GluN2A/GluN2B NMDA receptors

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