Pharmacological properties of homomeric and heteromeric GluR1o and GluR3o receptors

Nielsen, Brian S.; Banke, Tue G.; Schousboe, Arne; Pickering, Darryl S.

doi:10.1016/s0014-2999(98)00668-2

Cited by 25 publications

(24 citation statements)

References 53 publications

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“…The affinity of KA at the (Y702F)GluR2-S1S2J construct (K i ϭ 624 Ϯ 23 nM, n H ϭ 1.05 Ϯ 0.09, n ϭ 3) (Fig. 3A) is similar to that at GluR3 o (K i ϭ 1980 nM; (Nielsen et al, 1998)). However, the K i values of (S)-CPW399 and KA at (Y702F)GluR2-S1S2J versus GluR3 o , respectively, were statistically significantly different.…”

Section: Resultsmentioning

confidence: 72%

“…Samples were filtered onto Millipore (Billerica, MA) 0.22 m GSWP nitrocellulose filters; the filters were washed twice with 2 ml of nonradiolabeled assay buffer, and radioactivity was determined by scintillation counting. Data were analyzed using Grafit v3.00 (Erithacus Software Ltd., Horley, UK) and fit as described previously (Nielsen et al, 1998) to determine Hill coefficient and K i . The K d values of (R,S)- [5-methyl-3 H]AMPA at GluR2-S1S2J (12.8 nM) and (Y702F)GluR2-S1S2J (17.1 nM) were determined previously (Hogner et al, 2002).…”

Section: Structure Analysis and Figure Preparationmentioning

confidence: 99%

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Tyr702 Is an Important Determinant of Agonist Binding and Domain Closure of the Ligand-Binding Core of GluR2

Frandsen

Pickering²,

Vestergaard³

et al. 2004

Mol Pharmacol

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Ionotropic glutamate receptors mediate most rapid excitatory synaptic transmission in the mammalian central nervous system, and their involvement in neurological diseases has stimulated widespread interest in their structure and function. Despite a large number of agonists developed so far, few display selectivity among (S)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl) propionic acid (AMPA)-receptor subtypes. The present study provides X-ray structures of the glutamate receptor 2 (GluR2)-selective partial agonist (S)-2-amino-3-(1,3,5,6,7-pentahydro-2,4-dioxocyclopenta[e] pyrimidin-1-yl) propanoic acid [(S)-CPW399] in complex with the ligand-binding core of GluR2 (GluR2-S1S2J) and with a (Y702F)GluR2-S1S2J mutant. In addition, the structure of the nonselective partial agonist kainate in complex with (Y702F)GluR2-S1S2J was determined. The results show that the selectivity of (S)-CPW399 toward full-length GluR2 relative to GluR3 is reflected in the binding data on the two soluble constructs, allowing the use of (Y702F)GluR2-S1S2J as a model system for studying GluR2/GluR3 selectivity. Structural comparisons suggest that selectivity arises from disruption of a watermediated network between ligand and receptor. A D1-D2 domain closure occurs upon agonist binding. (S)-CPW399 and kainate induce greater domain closure in the Y702F mutant, indicating that these partial agonists here act in a manner more reminiscent of full agonists. Both kainate and (S)-CPW399 exhibited higher efficacy at (Y702F)GluR2(Q) i than at wild-type GluR2(Q) i . Whereas an excellent correlation exists between domain closure and efficacy of a range of agonists at full-length GluR2 determined by electrophysiology in Xenopus laevis oocytes, a direct correlation between agonist induced domain closure of (Y702F)GluR2-S1S2J and efficacy at the GluR3 receptor is not observed. Although it clearly controls selectivity, mutation of this residue alone is insufficient to explain agonist-induced conformational rearrangements occurring in this variant.Binding of (S)-glutamate to ionotropic glutamate receptors (iGluRs) is a key step in the predominant mechanism of rapid excitatory synaptic transmission among nerve cells within the mammalian central nervous system. iGluRs are important in the development and function of the central nervous system and are implicated in learning and memory formation. Furthermore, iGluRs also seem to be associated with certain neurological and psychiatric diseases (e.g., Alzheimer-type diseases, Parkinson's disease, epilepsy, stroke, amyotrophic lateral sclerosis, and schizophrenia). Therefore, the iGluRs are considered potential drug targets (Dingledine et al., 1999;Brä uner-Osborne et al., 2000). The iGluRs have been divided into three different classes: the (S)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl) propionic acid (AMPA), The structures reported in this article have been deposited within the Protein Databank with accession numbers 1SYH, 1SYI, and 1XHY.Article, publication date, and citation information can be found at ...

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Section: Resultsmentioning

confidence: 72%

Section: Structure Analysis and Figure Preparationmentioning

confidence: 99%

Tyr702 Is an Important Determinant of Agonist Binding and Domain Closure of the Ligand-Binding Core of GluR2

Frandsen

Pickering²,

Vestergaard³

et al. 2004

Mol Pharmacol

Self Cite

View full text Add to dashboard Cite

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“…Data were analyzed using Grafit version 3.00 (Erithacus Software Ltd., Horley, UK) and fit as previously described (see Equations 3 and 4 in Ref. 27) to determine the Hill coefficient (n H ) and K i . K d of the radioligand (1.91 nM) was previously determined (9).…”

Section: Methodsmentioning

confidence: 99%

Full Domain Closure of the Ligand-binding Core of the Ionotropic Glutamate Receptor iGluR5 Induced by the High Affinity Agonist Dysiherbaine and the Functional Antagonist 8,9-Dideoxyneodysiherbaine

Frydenvang

Lash

Naur

et al. 2009

Journal of Biological Chemistry

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“…The italic letters in parentheses indicate the RNA-edited isoforms of the subunits used. The IC 50 , Hill coefficient, and K i values for 1 were evaluated as previously described (35).…”

Section: Pharmacologymentioning

confidence: 99%

Discovery of a New Class of Ionotropic Glutamate Receptor Antagonists by the Rational Design of (2S,3R)-3-(3-Carboxyphenyl)-pyrrolidine-2-carboxylic Acid

Larsen

Venskutonytė

Valadés

et al. 2010

ACS Chem. Neurosci.

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The kainic acid (KA) receptors belong to the class of glutamate (Glu) receptors in the brain and constitute a promising target for the treatment of neurological and/ or psychiatric diseases such as schizophrenia, major depression, and epilepsy. Five KA subtypes have been identified and named GluK1-5. In this article, we present the discovery of (2S,3R)-3-(3-carboxyphenyl)-pyrrolidine-2-carboxylic acid (1) based on a rational design process. Target compound 1 was synthesized by a stereoselective strategy in 10 steps from commercially available starting materials. Binding affinities of 1 at native ionotropic Glu receptors were determined to be in the micromolar range (AMPA, 51 μM; KA, 22 μM; NMDA 6 μM), with the highest affinity for cloned homomeric KA receptor subtypes GluK1,3 (3.0 and 8.1 μM, respectively). Functional characterization of 1 by two electrode voltage clamp (TEVC) electrophysiology at a nondesensitizing mutant of GluK1 showed full competitive antagonistic behavior with a K b of 11.4 μM.

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Pharmacological properties of homomeric and heteromeric GluR1o and GluR3o receptors

Cited by 25 publications

References 53 publications

Tyr702 Is an Important Determinant of Agonist Binding and Domain Closure of the Ligand-Binding Core of GluR2

Tyr702 Is an Important Determinant of Agonist Binding and Domain Closure of the Ligand-Binding Core of GluR2

Full Domain Closure of the Ligand-binding Core of the Ionotropic Glutamate Receptor iGluR5 Induced by the High Affinity Agonist Dysiherbaine and the Functional Antagonist 8,9-Dideoxyneodysiherbaine

Discovery of a New Class of Ionotropic Glutamate Receptor Antagonists by the Rational Design of (2S,3R)-3-(3-Carboxyphenyl)-pyrrolidine-2-carboxylic Acid

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