title: A pharmacological profile of the high-affinity GluK5 kainate receptor.
abstract: Mouse GluK5 was expressed in Sf9 insect cells and radiolabelled with [(3)H]-kainate in receptor binding assays (Kd=6.9nM). Western immunoblotting indicated an Sf9 GluK5 band doublet corresponding to the glycosylated (128kDa) and deglycosylated (111kDa) protein, which was identical to the band pattern of native rat brain GluK5. A pharmacological profile of the high-affinity kainate receptor GluK5 is described which is distinct from the profiles of other kainate receptors (GluK1-3). The 27 tested ligands generally show a preferential affinity to GluK1 over GluK5, the exceptions being: dihydrokainate, (S)-5-fluorowillardiine, (S)-glutamate and quisqualate, where the affinity is similar at GluK1 and GluK5. In contrast, quisqualate shows 40-fold higher affinity at GluK5 over GluK3 whereas (S)-1-(2'-amino-2'-caboxyethyl)thienol[3,4-d]pyrimidin-2,4-dione (NF1231), (RS)-2-amino-3-(5-tert-butyl-3-hydroxyisoxazol-4-yl)propionate (ATPA), dihydrokainate and (2S,4R)-4-methyl-glutamate (SYM2081) have higher affinity at GluK3 compared to GluK5. Since some studies have indicated that GluK5 is associated with various diseases in the central nervous system (e.g. schizophrenia, temporal lobe epilepsy, bipolar disorder), selective GluK5 ligands could have therapeutic potential. The distinct pharmacological profile of GluK5 suggests that it would be possible to design ligands with selectivity towards GluK5.
authors.affiliation: Dept. of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Jagtvej 160, DK-2100 Copenhagen, Denmark.
authors.forename: Stine
authors.initials: S
authors.lastname: Møllerud
authors.affiliation: Dept. of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Jagtvej 160, DK-2100 Copenhagen, Denmark.
authors.forename: Jette Sandholm
authors.initials: JS
authors.lastname: Kastrup
authors.affiliation: Dept. of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Jagtvej 160, DK-2100 Copenhagen, Denmark. Electronic address: picker@sund.ku.dk.
authors.forename: Darryl S
authors.initials: DS
authors.lastname: Pickering
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D015195:Drug Design; D006031:Glycosylation; D007700:Kinetics; D008024:Ligands; D051379:Mice; D021122:Protein Subunits / Q000737:chemistry / Q000378:metabolism; D018092:Kainic Acid Receptors / Q000737:chemistry / Q000378:metabolism*; D061987:Sf9 Cells; D018411:Spodoptera
chemical_list: D008024:Ligands; D021122:Protein Subunits; D018092:Kainic Acid Receptors
keywords: AMPA, PubChem CID: 1221; ATPA, PubChem CID: 2253; Affinity; CNQX, PubChem CID: 3721046; Domoic acid, PubChem CID: 5282253; Glycosylation; Ionotropic glutamate receptor; Kainic acid, PubChem CID: 10255; Kinetics; L-Glutamic acid, PubChem CID: 33032; Quisqualic acid, PubChem CID: 40539; Radioligand binding; SYM2081, PubChem CID: 21117106; Sf9; UBP310, PubChem CID: 6420160; Willardiine, PubChem CID: 440053