Defining the structural relationship between kainate-receptor deactivation and desensitization

Dawe, G. Brent; Musgaard, Maria; Andrews, E. D.; Daniels, Bryan A.; Aurousseau, Mark; Biggin, Philip C.; Bowie, Derek

doi:10.1038/nsmb.2654

Cited by 36 publications

(70 citation statements)

References 53 publications

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“…The current study clearly shows that (−)-PPDA is a general antagonist that acts on all of the l -glutamate-binding iGluR subunits. A recent study has shown that the Tyr506Cys/Leu768Cys mutations in GluK1 receptors desynchronize receptor activation (Dawe et al, 2013). However, the overall interpretation that (−)-PPDA acts on GluK1 receptors with comparable potency to the GluN1/GluN2A NMDA receptors should remain intact.…”

Section: Resultsmentioning

confidence: 99%

Structural Insights into Competitive Antagonism in NMDA Receptors

Jespersen

Tajima

Fernández-Cuervo

et al. 2014

Neuron

121

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Summary There has been a great level of enthusiasm to down-regulate overactive N-methyl-d-aspartate (NMDA) receptors to protect neurons from excitotoxicity. NMDA receptors play pivotal roles in basic brain development and functions as well as in neurological disorders and diseases. However, mechanistic understanding of antagonism in NMDA receptors is limited due to complete lack of antagonist-bound structures for the l-glutamate-binding GluN2 subunits. Here we report the crystal structures of GluN1/GluN2A NMDA receptor ligand-binding domain (LBD) heterodimers in complex with GluN1- and GluN2-targeting antagonists. The crystal structures reveal that the antagonists, D-(−)-2-Amino-5-phosphonopentanoic acid (d-AP5) and 1-(Phenanthrene-2-carbonyl)piperazine-2,3-dicarboxylic acid (PPDA), have discrete binding modes and mechanisms for opening of the bilobed architecture of GluN2A LBD compared to the agonist-bound form. The current study shows distinct ways by which the conformations of NMDA receptor LBDs may be controlled and coupled to receptor inhibition and provides possible strategies to develop therapeutic compounds with higher subtype-specificity.

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Section: Resultsmentioning

confidence: 99%

Structural Insights into Competitive Antagonism in NMDA Receptors

Jespersen

Tajima

Fernández-Cuervo

et al. 2014

Neuron

121

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“…Furthermore, KAR desensitization is thought to be mediated in part by unbinding of sodium prior to that of glutamate, leading to LBD dimer interface rupture (Dawe et al . ).…”

Section: Discussionmentioning

confidence: 97%

Identification of critical functional determinants of kainate receptor modulation by auxiliary protein Neto2

Griffith

Swanson

2015

The Journal of Physiology

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Key pointsr Kainate receptors (KARs) are ionotropic glutamate receptors (iGluRs) that modulate synaptic transmission and intrinsic neuronal excitability.r KARs associate with the auxiliary proteins neuropilin-and tolloid-like 1 and 2 (Neto1 and Neto2), which act as allosteric modulators of receptor function impacting all biophysical properties of these receptors studied to date. r M3-S2 linkers play a critical role in KAR gating; we found that individual residues in these linkers bidirectionally influence Neto2 modulation of KAR desensitization in an agonist specific manner.r We also identify the D1 dimer interface as a novel site of Neto2 modulation and functionally correlate the actions of Neto2 modulation of desensitization with modulation of cation sensitivity.r We identify these domains as determinants of Neto2 modulation. Thus, our work contributes to the understanding of auxiliary subunit modulation of KAR function and could aid the development of KAR-specific modulators to alter receptor function.Abstract Kainate receptors (KARs) are important modulators of synaptic transmission and intrinsic neuronal excitability in the CNS. Their activity is shaped by the auxiliary proteins Neto1 and Neto2, which impact KAR gating in a receptor subunit-and Neto isoform-specific manner. The structural basis for Neto modulation of KAR gating is unknown. Here we identify the M3-S2 gating linker as a critical determinant contributing to Neto2 modulation of KARs. M3-S2 linkers control both the valence and magnitude of Neto2 modulation of homomeric GluK2 receptors. Furthermore, a single mutation in this domain abolishes Neto2 modulation of heteromeric receptor desensitization. Additionally, we found that cation sensitivity of KAR gating is altered by Neto2 association, suggesting that stability of the D1 dimer interface in the ligand-binding domain (LBD) is an important determinant of Neto2 actions. Moreover, modulation of cation sensitivity was eliminated by mutations in the M3-S2 linkers, thereby correlating the action of Neto2 at these structurally discrete sites on receptor subunits. These results demonstrate that the KAR M3-S2 linkers and LBD dimer interface are critical determinants for Neto2 modulation of receptor function and identify these domains as potential sites of action for the targeted development of KAR-specific modulators that alter the function of auxiliary proteins in native receptors. Abbreviations ATD, amino terminal domain; AMPAR, AMPA receptor; CUB, C1r/C1s-Uegf-BMP; eGFP, enhanced green florescent protein; iGluR, ionotropic glutamate receptor; KAR, kainate receptor; LBD, ligand binding domain; NMDAR, NMDA receptor; Neto, neuropilin-and tolloid-like; TARP, transmembrane AMPA receptor regulatory protein.

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“…The LBD binds agonists (including glutamate), antagonists and channel modulators; it is connected to the NTD and TMD layers via peptide linkers. A host of functional and structural data (Mayer, 2006;Traynelis et al, 2010) combined with simulations of individual receptor domains (Arinaminpathy et al, 2006;Bjerrum et al, 2008;Dawe et al, 2013;Dutta et al, 2012;Lau et al, 2011;Lau et al, 2013;Sukumaran et al, 2011;Zhu et al, 2013) has provided a framework of how glutamate-docking to the LBD ‘clamshell’ ultimately triggers ion channel opening followed by receptor deactivation (closure in response to ligand unbinding), or desensitization (closure with ligand bound). Yet, an understanding of how the three domain layers communicate in the intact receptor to ultimately gate the ion channel is currently not well understood.…”

Section: Introductionmentioning

confidence: 99%

Cooperative Dynamics of Intact AMPA and NMDA Glutamate Receptors: Similarities and Subfamily-Specific Differences

et al. 2015

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Summary Ionotropic glutamate receptors (iGluRs) are tetrameric ion channels that mediate excitatory neurotransmission. Recent structures of AMPA and NMDA receptors permit a comparative analysis of whole-receptor dynamics for the first time. Despite substantial differences in the packing of their two-domain extracellular region, the two iGluRs share similar dynamics, elucidated by elastic network models. Motions accessible to either structure enable conformational interconversion, such as compression of the AMPAR towards the more tightly packed NMDAR conformation, which has been linked to allosteric regulation. Pivoting motions coupled to concerted rotations of the transmembrane ion channel are prominent between dimers of distal N-terminal domains in the loosely-packed AMPAR. The occurrence and functional relevance of these motions is verified by cross-linking experiments designed to probe the computationally predicted distance changes. Together with the identification of hot-spot residues acting as mediators of allosteric communication, our data provide a glimpse into the dynamic spectrum of iGluRs.

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Defining the structural relationship between kainate-receptor deactivation and desensitization

Cited by 36 publications

References 53 publications

Structural Insights into Competitive Antagonism in NMDA Receptors

Structural Insights into Competitive Antagonism in NMDA Receptors

Identification of critical functional determinants of kainate receptor modulation by auxiliary protein Neto2

Cooperative Dynamics of Intact AMPA and NMDA Glutamate Receptors: Similarities and Subfamily-Specific Differences

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