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, Karla; Lash, L. Leanne; Naur, Peter; Postila, Pekka A.; Pickering, Darryl S.; Smith, Caleb M.; Gajhede, Michael; Sasaki, Makoto; Sakai, Ryuichi; Pentikäinen, Olli T.; Swanson, Geoffrey T.; Kastrup, J.S.

doi:10.1074/jbc.m808547200

Cited by 54 publications

(96 citation statements)

References 46 publications

(61 reference statements)

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“…H͔kainate at recombinant kainate receptors (Lash et al, 2008). o EC 50 for MSVIII-19 at GluK1 recombinant receptors expressed in HEK293 cells treated with Con A. MSVIII-19 failed to displace kainate from recombinant GluK2 expressed in HEK293 cells (Frydenvang et al, 2009). …”

Section: Egebjerg Et Al (1991)mentioning

confidence: 96%

“…The neodysiherbaine analogs 8-deoxy-neodysiherbaine, 9-deoxy-neodysiherbaine, and MSVIII-19 show nanomolar affinity for GluK1 and Ͼ1000-fold selectivity over GluK2, GluK3, and GluK5, with 8-and 9-deoxy-neodysiherbaine acting as a partial and full agonists, respectively (Lash et al, 2008). MSVIII-19 was originally reported as a GluK1 antagonist (Sanders et al, 2005), but crystallographic studies revealed that it induces full domain closure of the GluK1 LBD, prompting further functional studies that showed it to be an agonist of extremely low efficacy (Frydenvang et al, 2009)…”

Section: Glutamate Receptor Ion Channelsmentioning

confidence: 99%

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Glutamate Receptor Ion Channels: Structure, Regulation, and Function

et al. 2010

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Section: Egebjerg Et Al (1991)mentioning

confidence: 96%

Section: Glutamate Receptor Ion Channelsmentioning

confidence: 99%

Glutamate Receptor Ion Channels: Structure, Regulation, and Function

et al. 2010

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“…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: 91%

“…In this model, full agonists are more effective activators than partial agonists because they promote greater domain closure. However, more recent work on both AMPARs and KARs has questioned the validity of this idea since a clear relationship between agonist efficacy and the extent of domain closure was not able to be established (Zhang et al, 2008;Fay et al, 2009;Frydenvang et al, 2009;Birdsey-Benson et al, 2010). Given this, we reasoned that regions outside the agonistbinding pocket, such as the dimer interface, may have a more prominent role in fine tuning agonist efficacy.…”

Section: Disruption To the Dimer Interface Affects Agonist Responsivementioning

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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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

Cited by 54 publications

References 46 publications

Glutamate Receptor Ion Channels: Structure, Regulation, and Function

Glutamate Receptor Ion Channels: Structure, Regulation, and Function

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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