Functional Characterization and In Silico Docking of Full and Partial GluK2 Kainate Receptor Agonists

Fay, Anne-Marie L.; Corbeil, Christopher R.; Brown, Patricia M.G.E.; Moitessier, Nicolas; Bowie, Derek

doi:10.1124/mol.108.054254

Cited by 19 publications

(32 citation statements)

References 37 publications

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“…2a and Supplementary Fig. S3), as observed for mammalian receptors, but not for GluR0 5,11,12,14 . For aspartate and kainate, the difference in agonist response seems to be due to a shift in potency as the currents extracted from the fit at the EC 50 concentration are in the same range as for Glu ( Supplementary Fig.…”

Section: Functional Characterization When We Expressed Avglur1 Inmentioning

confidence: 58%

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A modern ionotropic glutamate receptor with a K+ selectivity signature sequence

2011

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Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system and gates non-selective cation channels. The origins of glutamate receptors are not well understood as they differ structurally and functionally from simple bacterial ligand-gated ion channels. Here we report the discovery of an ionotropic glutamate receptor that combines the typical eukaryotic domain architecture with the 'TXVGYG' signature sequence of the selectivity filter found in K + channels. This receptor exhibits functional properties intermediate between bacterial and eukaryotic glutamate-gated ion channels, suggesting a link in the evolution of ionotropic glutamate receptors.

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Section: Functional Characterization When We Expressed Avglur1 Inmentioning

confidence: 58%

“…S2). These amino acids do not gate AMPA and kainate receptors but serve as agonists of NMDA receptors 5,[11][12][13] . AvGluR1 was also gated by iGluR agonists kainate and AMPA ( Fig.…”

Section: Functional Characterization When We Expressed Avglur1 Inmentioning

confidence: 99%

A modern ionotropic glutamate receptor with a K+ selectivity signature sequence

2011

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“…Agonist solutions were prepared by dissolving the agonist in the appropriate external solution and adjusting the pH with the corresponding hydroxide solution. Agonist concentrations were selected as determined by Fay et al (2009), made from concentrated 10ϫ stock solutions, stored at Ϫ20°, and thawed before use.…”

Section: Methodsmentioning

confidence: 99%

“…At AMPA-and kainate (KA)-type ionotropic glutamate receptors (iGluRs), initial studies proposed that agonist efficacy resides in the conformations adopted by the agonist-binding domain (ABD) with full agonists more effective at promoting domain closure than partial agonists (Armstrong and Gouaux, 2000;Jin et al, 2003;Mayer, 2005). However, this long-held view has been challenged by more recent work on AMPA receptors (AMPARs) (Zhang et al, 2006(Zhang et al, , 2008 and kainate receptors (KARs) (Fay et al, 2009;Frydenvang et al, 2009) that has failed to report a clear relationship between agonist efficacy and domain closure. From their work on AMPARs, Zhang et al (2006Zhang et al ( , 2008 have proposed that agonist efficacy is determined by the stability of the closedcleft conformation of the ABD.…”

Section: Introductionmentioning

confidence: 99%

Cations But Not Anions Regulate the Responsiveness of Kainate Receptors

MacLean

Wong²,

Fay³

et al. 2011

J. Neurosci.

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Kainate-selective ionotropic glutamate receptors are unique among ligand-gated ion channels in their obligate requirement of external anions and cations for activation. Although it is established that the degree of kainate receptor (KAR) activation is shaped by the chemical nature of the agonist molecule, the possible complementary role of external ions has yet to be examined. Here we show that external cations but not anions regulate the responsiveness to a range of full and partial agonists acting on rat GluK2 receptors. This observation is unexpected as previous work has assumed anions and cations affect KARs in an identical manner through functionally coupled binding sites. However, our data demonstrate that anion-and cation-binding pockets behave discretely. We suggest cations uniquely regulate a pregating or flipping step that impacts the closed-cleft stability of the agonist-binding domain (ABD). This model departs from a previous proposal that KAR agonist efficacy is governed by the degree of closure elicited in the ABD by ligand binding. Our findings are, however, in line with recent studies on Cys-loop ligand-gated ion channels suggesting that the "flipping" mechanism has been conserved by structurally diverse ligand-gated ion channel families as a common means of regulating neurotransmitter behavior.

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“…For example, mutants have been characterized where partial agonists induce complete cleftclosure (Zhang et al, 2008), or where efficacy is related to D2 domain twisting (Birdsey-Benson et al, 2010). For kainate receptor subunits the correlation between cleft-closure and efficacy has also been questioned, with partial agonists again inducing complete cleft-closure in either x-ray structures (Frydenvang et al, 2009) or modeling studies (Fay et al, 2009). In this context, our identification of ligand-specific changes in LBD dimer conformation in the GluK2 Figure 5.…”

Section: Ligand-specific Shifts In Dimer Conformationmentioning

confidence: 99%

Conformational Flexibility of the Ligand-Binding Domain Dimer in Kainate Receptor Gating and Desensitization

Nayeem¹,

Mayans²,

Green³

2011

J. Neurosci.

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AMPA-and kainate (KA)-selective ionotropic glutamate receptors (iGluRs) respond to agonist by opening (gating), then closing (desensitizing) in quick succession. Gating has been linked to agonist-induced changes within the ligand-binding domain (LBD), and desensitization to rearrangement of a dimer formed by neighboring LBDs. To explore the role of dimer conformation in both gating and desensitization, we compared the conformational effects of two kainate receptor mutants. The first, GluK2-D776K, blocks desensitization of macroscopic current responses ("macroscopic desensitization"). The second, GluK2-M770K, accelerates macroscopic desensitization and eliminates the effects of external ions on channel kinetics. Using structures determined by x-ray crystallography, we found that in both mutants the introduced lysines act as tethered cations, displacing sodium ions from their binding sites within the dimer interface. This results in new inter-and intra-protomer contacts in D776K and M770K respectively, explaining the effects of these mutations on dimer stability and desensitization kinetics. Further, chloride binding was unaffected by the M770K mutation, even though binding of sodium ions has been proposed to promote dimer stability by stabilizing anion binding. This suggests sodium binding may affect receptor function more directly than currently supposed. Notably, we also observed a ligand-specific shift in dimer conformation when comparing LBD dimers in complex with glutamate or the partial agonist KA, revealing a previously unidentified role for dimer orientation in iGluR gating.

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Functional Characterization and In Silico Docking of Full and Partial GluK2 Kainate Receptor Agonists

Cited by 19 publications

References 37 publications

A modern ionotropic glutamate receptor with a K+ selectivity signature sequence

A modern ionotropic glutamate receptor with a K+ selectivity signature sequence

Cations But Not Anions Regulate the Responsiveness of Kainate Receptors

Conformational Flexibility of the Ligand-Binding Domain Dimer in Kainate Receptor Gating and Desensitization

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