Abstract
The GluD2 receptor is a fundamental component of postsynaptic sites in Purkinje neurons, and is required for normal cerebellar function. GluD2 and the closely related GluD1 are classified as members of the ionotropic glutamate receptor (iGluR) superfamily on the basis of sequence similarity, but do not bind L-glutamate. The amino acid neurotransmitter D-Ser is a GluD2 receptor ligand, and endogenous D-Ser signaling through GluD2 has recently been shown to regulate endocytosis of a-amino- 3-hydroxy-5-methyl-4-isoxazolepropionic acid-type iGluRs during synaptic plasticity in the cerebellum, such as long-term depression. Here, we investigate the pharmacology of the orthosteric binding site in GluD2 by examining the activity of analogs of D-Ser and GluN1 glycine site competitive antagonists at GluD2 receptors containing the lurcher mutation (GluD2LC), which promotes spontaneous channel activation. We identify several compounds that modulate GluD2LC, including a halogenated alanine analog as well as the kynurenic acid analog 7-chloro- 4-oxo-1H-quinoline-2-carboxylic acid (7-chlorokynurenic acid; 7-CKA). By correlating thermodynamic and structural data for 7-CKA binding to the isolated GluD2 ligand binding domain (GluD2-LBD), we find that binding 7-CKA to GluD2-LBD differs from D-Ser by inducing an intermediate cleft closure of the clamshell-shaped LBD. The GluD2 ligands identified here can potentially serve as a starting point for development of GluD2- selective ligands useful as tools in studies of the signaling role of the GluD2 receptor in the brain.
| Original language | English |
|---|---|
| Pages (from-to) | 253-262 |
| Number of pages | 10 |
| Journal | Molecular Pharmacology |
| Volume | 89 |
| Issue number | 2 |
| DOIs | |
| State | Published - Feb 1 2016 |
| Externally published | Yes |
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All Science Journal Classification (ASJC) codes
- Pharmacology
- Molecular Medicine
Cite this
Pharmacology and structural analysis of ligand binding to the orthosteric site of glutamate-like GluD2 receptors. / Kristensen, Anders S.; Hansen, Kasper B.; Naur, Peter; Olsen, Lars; Kurtkaya, Natalie L.; Dravid, Shashank M.; Kvist, Trine; Yi, Feng; Pøhlsgaard, Jacob; Clausen, Rasmus P.; Gajhede, Michael; Kastrup, Jette S.; Traynelis, Stephen F.
In: Molecular Pharmacology, Vol. 89, No. 2, 01.02.2016, p. 253-262.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Pharmacology and structural analysis of ligand binding to the orthosteric site of glutamate-like GluD2 receptors
AU - Kristensen, Anders S.
AU - Hansen, Kasper B.
AU - Naur, Peter
AU - Olsen, Lars
AU - Kurtkaya, Natalie L.
AU - Dravid, Shashank M.
AU - Kvist, Trine
AU - Yi, Feng
AU - Pøhlsgaard, Jacob
AU - Clausen, Rasmus P.
AU - Gajhede, Michael
AU - Kastrup, Jette S.
AU - Traynelis, Stephen F.
PY - 2016/2/1
Y1 - 2016/2/1
N2 - The GluD2 receptor is a fundamental component of postsynaptic sites in Purkinje neurons, and is required for normal cerebellar function. GluD2 and the closely related GluD1 are classified as members of the ionotropic glutamate receptor (iGluR) superfamily on the basis of sequence similarity, but do not bind L-glutamate. The amino acid neurotransmitter D-Ser is a GluD2 receptor ligand, and endogenous D-Ser signaling through GluD2 has recently been shown to regulate endocytosis of a-amino- 3-hydroxy-5-methyl-4-isoxazolepropionic acid-type iGluRs during synaptic plasticity in the cerebellum, such as long-term depression. Here, we investigate the pharmacology of the orthosteric binding site in GluD2 by examining the activity of analogs of D-Ser and GluN1 glycine site competitive antagonists at GluD2 receptors containing the lurcher mutation (GluD2LC), which promotes spontaneous channel activation. We identify several compounds that modulate GluD2LC, including a halogenated alanine analog as well as the kynurenic acid analog 7-chloro- 4-oxo-1H-quinoline-2-carboxylic acid (7-chlorokynurenic acid; 7-CKA). By correlating thermodynamic and structural data for 7-CKA binding to the isolated GluD2 ligand binding domain (GluD2-LBD), we find that binding 7-CKA to GluD2-LBD differs from D-Ser by inducing an intermediate cleft closure of the clamshell-shaped LBD. The GluD2 ligands identified here can potentially serve as a starting point for development of GluD2- selective ligands useful as tools in studies of the signaling role of the GluD2 receptor in the brain.
AB - The GluD2 receptor is a fundamental component of postsynaptic sites in Purkinje neurons, and is required for normal cerebellar function. GluD2 and the closely related GluD1 are classified as members of the ionotropic glutamate receptor (iGluR) superfamily on the basis of sequence similarity, but do not bind L-glutamate. The amino acid neurotransmitter D-Ser is a GluD2 receptor ligand, and endogenous D-Ser signaling through GluD2 has recently been shown to regulate endocytosis of a-amino- 3-hydroxy-5-methyl-4-isoxazolepropionic acid-type iGluRs during synaptic plasticity in the cerebellum, such as long-term depression. Here, we investigate the pharmacology of the orthosteric binding site in GluD2 by examining the activity of analogs of D-Ser and GluN1 glycine site competitive antagonists at GluD2 receptors containing the lurcher mutation (GluD2LC), which promotes spontaneous channel activation. We identify several compounds that modulate GluD2LC, including a halogenated alanine analog as well as the kynurenic acid analog 7-chloro- 4-oxo-1H-quinoline-2-carboxylic acid (7-chlorokynurenic acid; 7-CKA). By correlating thermodynamic and structural data for 7-CKA binding to the isolated GluD2 ligand binding domain (GluD2-LBD), we find that binding 7-CKA to GluD2-LBD differs from D-Ser by inducing an intermediate cleft closure of the clamshell-shaped LBD. The GluD2 ligands identified here can potentially serve as a starting point for development of GluD2- selective ligands useful as tools in studies of the signaling role of the GluD2 receptor in the brain.
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U2 - 10.1124/mol.115.100909
DO - 10.1124/mol.115.100909
M3 - Article
VL - 89
SP - 253
EP - 262
JO - Molecular Pharmacology
JF - Molecular Pharmacology
SN - 0026-895X
IS - 2
ER -