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.
N1 - Funding Information:
This work was supported by the National Institute of Mental Health [Grant R21-MH062204 to S.F.T.]; National Institute of General Medicine [Grant P20- GM103546 to K.B.H.]; the National Alliance for Research on Schizophrenia and Depression [to S.F.T.]; Alfred Benzon Foundation [grants to A.S.K.. and K.B.H.]; the Danish Medical Research Council [grants to A.S.K., J.S.K., L.O., M.G., and P.N.]; the GluTarget Programme of Excellence at the University of Copenhagen [grant to T.K., J.S.K., and A.S.K.]; the Danish Ministry of Science, Innovation and Higher Education’s EliteForsk Programme [travel grant to T.K.], the Lundbeck Foundation [grant to J.S.K., L.O., M.G., J.P., and P.N.A.]; the Carlsberg Foundation [grant to J.S.K., L.O., and M.G.]; Danscatt [to J.S.K., L.O., M.G., and P.N.A.]; and a University of Copenhagen Drug Research Academy stipend [to P.N.A.]. The authors thank the staff at MAX-laboratory for help during data collection.
Publisher Copyright:
Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.
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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UR - http://www.scopus.com/inward/citedby.url?scp=84958248947&partnerID=8YFLogxK
U2 - 10.1124/mol.115.100909
DO - 10.1124/mol.115.100909
M3 - Article
C2 - 26661043
AN - SCOPUS:84958248947
VL - 89
SP - 253
EP - 262
JO - Molecular Pharmacology
JF - Molecular Pharmacology
SN - 0026-895X
IS - 2
ER -