Functional Characterization of Tet-AMPA [Tetrazolyl-2-amino-3-(3-hydroxy-5-methyl- 4-isoxazolyl)propionic Acid] Analogues at Ionotropic Glutamate Receptors GluR1−GluR4. The Molecular Basis for the Functional Selectivity Profile of 2-Bn-Tet-AMPA

Jensen, Anders A.; Christesen, Thomas; Bølcho, Ulrik; Greenwood, Jeremy R.; Postorino, G; Vogensen, Stine B.; Johansen, Tommy N.; Egebjerg, Jan; Bräuner‐Osborne, Hans; Clausen, Rasmus P.

doi:10.1021/jm070532r

Cited by 19 publications

(26 citation statements)

References 18 publications

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“…Agonists such as 6-aza substituted willardiine derivatives display an increased potency for GluR4 receptors (52, 53), and others like 2-Bn-Tet-AMPA exhibit a 40-fold increased potency at GluR4 receptors compared to GluR1/2 receptors (54). An examination of the ligand-binding sub-pockets in the vicinity of the functional groups that are changed did not show any obvious stereochemical differences between GluR4 and GluR2 structures that would account for these results.…”

Section: Resultsmentioning

confidence: 99%

Correlating AMPA Receptor Activation and Cleft Closure across Subunits: Crystal Structures of the GluR4 Ligand-Binding Domain in Complex with Full and Partial Agonists

et al. 2008

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AMPA receptors are glutamate-gated ion channels that are essential mediators of synaptic signals in the central nervous system. They form tetramers that are assembled as combinations of the subunits GluR1-4, each of which contains a ligand-binding domain (LBD). Crystal structures of the GluR2 LBD have revealed an agonist-binding cleft, which is located between two lobes and which acts like a Venus flytrap. In general, agonist efficacy is correlated with the extent of cleft closure. However, recent observations show that cleft closure is not the sole determinant of relative efficacy for glutamate receptors. In addition, these studies have focused on the GluR2 subunit, which is the specific target of a physiologically important RNA-editing modification in vivo. We therefore wished to test the generality of the cleft closure:efficacy correlation for other AMPA-R subunits. Here, we present crystal structures of the GluR4 flip LBD in complex with both full and partial agonists. As for GluR2, both agonists stabilize a closed-cleft conformation, and the partial agonist induces a smaller cleft closure than the full agonist. However, a detailed analysis of LBD:kainate interactions reveals the importance of subtle backbone conformational changes in the ligand-binding pocket in determining the magnitude of agonist-associated conformational changes. Furthermore, the GluR4 subunit exhibits a different correlation between receptor activation and LBD cleft closure than does GluR2. Keywordsionotropic glutamate receptor; AMPA receptor ion channel; GluR4 ligand-binding domain; X-ray crystallography; electrophysiology; subunit dimerization; relative agonist efficacy; conformational change Within the central nervous system, most fast excitatory synaptic signals are mediated by ionotropic glutamate receptors (iGluRs) that are selective for the synthetic agonist AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) (1). In addition to their role in neurotransmission, the AMPA receptors (AMPA-Rs) contribute to synaptic plasticity and are thus thought to play important roles in learning and memory (2). AMPA-Rs have also been † A.G. was supported in part by the John H. Copenhaver, Jr., and William H. Thomas, M.D., 1952 Fellowship Fund and AMPA-Rs are assembled as tetramers of subunits known as GluR1-GluR4. The composition of the receptors in a given neuron depends on which subunits are expressed, and on a variety of post-transcriptional modifications, including alternative splicing and RNA editing (reviewed in ref. 1). A particularly important modification involves the selective RNA editing of the mRNA encoding the GluR2 subunit, which converts a genetically encoded Gln codon common to all subunits to an Arg codon at position 586 in the mature sequence of GluR2. This editing is nearly 100% efficient in adults. Heteromeric channels that include edited GluR2-R subunits are the most common form of AMPA-R in vivo. They are non-rectifying and conduct predominantly monovalent cations. In contrast, AMPA-Rs that do not include...

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Section: Resultsmentioning

confidence: 99%

Correlating AMPA Receptor Activation and Cleft Closure across Subunits: Crystal Structures of the GluR4 Ligand-Binding Domain in Complex with Full and Partial Agonists

et al. 2008

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“…Cl-HIBO activates GluA1 and GluA2 with 275-to 1600-fold selectivity over GluA3 or GluA4, respectively. The agonist 2-benzyl-tetrazol-AMPA shows 40-fold selectivity for GluA4 over GluA1 (Jensen et al, 2007). Crystal structures of 2-benzyl-tetrazol-AMPA bound to the GluA2 LBD reveal that the benzyl group occupies a novel cavity opened up by movement of Met708 in GluA2, and the selectivity of 2-benzyl-tetrazol-AMPA is due to residues adjacent to this cavity (Val690 and Ala691), which are conserved in GluA2 to GluA4 but correspond to Met686 and Ile687 in GluA1 (Vogensen et al, 2007).…”

Section: Schiffer Et Al (1997)mentioning

confidence: 99%

Glutamate Receptor Ion Channels: Structure, Regulation, and Function

et al. 2010

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“…AMPA receptor agonists with preferences for GluA1/2 versus GluA3/4 and GluA1/2/3 versus GluA4, respectively. [7][8][9] 8-Me-4-AHCP (7) is a highly selective GluK1 agonist [10] (Scheme 2). X-ray crystallographic and mutational studies have disclosed that the selectivity of these ligands arises from interactions with different non-conserved parts of the receptorbinding pocket.…”

Section: Introductionmentioning

confidence: 99%

Partial Agonists and Subunit Selectivity at NMDA Receptors

Risgaard¹,

Hansen²,

Clausen³

2010

Chemistry A European J

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Subunit-selective ligands for glutamate receptors remains an area of interest as glutamate is the major excitatory neurotransmitter in the brain and involved in a number of diseased states in the central nervous system (CNS). Few subtype-selective ligands are known, especially among the N-methyl-D-aspartic acid (NMDA) receptor class. Development of these ligands seems to be a difficult task because of the conserved region in the binding site of the NMDA receptor subunits. A few scaffolds have been developed showing potential to differentiate between the NMDA receptors.

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Functional Characterization of Tet-AMPA [Tetrazolyl-2-amino-3-(3-hydroxy-5-methyl- 4-isoxazolyl)propionic Acid] Analogues at Ionotropic Glutamate Receptors GluR1−GluR4. The Molecular Basis for the Functional Selectivity Profile of 2-Bn-Tet-AMPA

Cited by 19 publications

References 18 publications

Correlating AMPA Receptor Activation and Cleft Closure across Subunits: Crystal Structures of the GluR4 Ligand-Binding Domain in Complex with Full and Partial Agonists

Correlating AMPA Receptor Activation and Cleft Closure across Subunits: Crystal Structures of the GluR4 Ligand-Binding Domain in Complex with Full and Partial Agonists

Glutamate Receptor Ion Channels: Structure, Regulation, and Function

Partial Agonists and Subunit Selectivity at NMDA Receptors

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