The N-terminal Domain Modulates α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) Receptor Desensitization

Möykkynen, Tommi; Coleman, Sarah K.; Semenov, Artur; Keinänen, Kari

doi:10.1074/jbc.m113.526301

Cited by 26 publications

(31 citation statements)

References 67 publications

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“…As a direct consequence of the subunit crossover or domain swapping, it is logical that a disruption of the dimer interface in both LBD dimers will destabilize the Y-shaped structure characteristic of resting and non-desensitizing conditions because there is no significant additional stabilization by other inter-subunit interfaces, such as between proximal BD subunits in the ATD layer or between proximal AC pairs in the LBD layer. Conversely, the crossover between ATD and LBD layers is most likely responsible for the slower onset of desensitization and a faster recovery from desensitization for GluA1-4 receptors with deleted ATDs (Moykkynen et al, 2014). Because each subunit within a LBD dimer is connected to a different ATD dimer, additional strain maybe exerted on the D1-D1 interface during activation, hence promoting D1-D1 separation and the disruption of the dimer interface.…”

Section: Resultsmentioning

confidence: 99%

Structure and Dynamics of AMPA Receptor GluA2 in Resting, Pre-Open, and Desensitized States

Dürr

Chen

Stein

et al. 2014

Cell

197

271

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Summary Ionotropic glutamate receptors (iGluRs) mediate the majority of fast excitatory signaling in the nervous system. Despite the profound importance of iGluRs in the nervous system, little is known about the structures and dynamics of intact receptors in distinct functional states. Here we elucidate the structures of the intact GluA2 AMPA receptor in an apo resting/closed state, in an activated/pre-open state bound with the partial agonists and a positive allosteric modulator and in a desensitized/closed state in complex with FW alone. To probe the conformational properties of these states, we carried out double electron-electron resonance experiments on cysteine mutants and cryo-electron microscopy studies. We show how agonist binding modulates the conformation of the ligand binding domain 'layer' of the intact receptors and how, upon desensitization, the receptor undergoes large conformational rearrangements of amino-terminal and ligand-binding domains. We define mechanistic principles by which to understand antagonism, activation and desensitization in AMPA iGluRs.

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Section: Resultsmentioning

confidence: 99%

Structure and Dynamics of AMPA Receptor GluA2 in Resting, Pre-Open, and Desensitized States

Dürr

Chen

Stein

et al. 2014

Cell

197

271

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“…By contrast, little or no ATD-mediated regulation is observed in non-NMDARs [59]. That is, the close juxtaposition of the ATDs to the LBDs in the NMDAR likely allows for the efficient propagation of conformational alterations in the ATD to the LBD and vice versa , whereas in non-NMDARs the ATD is too distant from the LBD to affect conformation or subunit arrangement in the LBD, as is evident from crystallographic and cryo-EM studies.…”

Section: The First Visualization Of Nmdar Heterotetramersmentioning

confidence: 99%

Emerging structural insights into the function of ionotropic glutamate receptors

Karakaş

Regan

Furukawa

2015

Trends in Biochemical Sciences

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Summary Ionotropic glutamate receptors (iGluRs) are ligand-gated ion channels that mediate excitatory neurotransmission crucial for brain development and function including learning and memory formation. Recently a wealth of structural studies on iGluRs, including AMPA receptors (AMPARs), kainate receptors, and NMDA receptors (NMDARs) became available.. These studies showed structures of non-NMDARs including AMPAR and kainate receptor in various functional states, thereby providing the first visual sense of how non-NMDAR iGluRs may function in the context of homotetramers. Furthermore, they provided the first view of heterotetrameric NMDAR ion channels, which illuminated the similarities with and differences from non-NMDARs, thus raising a mechanistic distinction between the two groups of iGluRs. Here we review mechanistic insights into iGluR functions gained through structural studies of multiple groups.

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“…Electrophysiology-Whole-cell patch clamp recordings and analysis of glutamate-triggered currents in transfected cells were carried out as previously described (22). In brief, recordings from AMPA receptors expressing HEK293 cells were done at a holding potential of Ϫ60 mV.…”

Section: Methodsmentioning

confidence: 99%

Aggregation Limits Surface Expression of Homomeric GluA3 Receptors

Coleman¹,

Hou²,

Willibald³

et al. 2016

Journal of Biological Chemistry

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AMPA receptors are glutamate-gated cation channels assembled from GluA1-4 subunits and have properties that are strongly dependent on the subunit composition. The subunits have different propensities to form homomeric or various heteromeric receptors expressed on cell surface, but the underlying mechanisms are still poorly understood. Here, we examined the biochemical basis for the poor ability of GluA3 subunits to form homomeric receptors, linked previously to two amino acid residues, Tyr-454 and Arg-461, in its ligand binding domain (LBD). Surface expression of GluA3 was improved by co-assembly with GluA2 but not with stargazin, a trafficking chaperone and modulator of AMPA receptors. The secretion efficiency of GluA2 and GluA3 LBDs paralleled the transport difference between the respective full-length receptors and was similarly dependent on Tyr-454/Arg-461 but not on LBD stability. In comparison to GluA2, GluA3 homomeric receptors showed a strong and Tyr-454/Arg-461-dependent tendency to aggregate both in the macroscopic scale measured as lower solubility in nonionic detergent and in the microscopic scale evident as the preponderance of hydrodynamically large structures in density gradient centrifugation and native gel electrophoresis. We conclude that the impaired surface expression of homomeric GluA3 receptors is caused by nonproductive assembly and aggregation to which LBD residues Tyr-454 and Arg-461 strongly contribute. This aggregation inhibits the entry of newly synthesized GluA3 receptors to the secretory pathway.␣-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors are tetrameric ligand-gated ion channels that mediate fast excitatory neurotransmission in vertebrate brain (1, 2). The functional properties of AMPA receptors, including channel kinetics, ion permeability, ligand pharmacology, and regulation, are determined by the subunit composition. AMPA receptors are built from four subunit types (GluA1-4), each expressed as multiple alternatively spliced and/or RNA-edited variants. Studies with native and recombinant receptors indicate that receptor assembly is not random but strongly favors certain subunit combinations (3, 4). The majority of native AMPA receptors are heteromers of edited GluA2 subunits with GluA1 or GluA3 subunits, forming channels that are impermeable to Ca 2ϩ and showing a linear current-voltage (I-V) relation (3, 5, 6). Minor native populations of homomeric AMPA receptors are formed by GluA1 or GluA4 subunits to produce inwardly rectifying and Ca 2ϩ -permeable channels (7,8).At present, the molecular logic underlying the formation and cellular processing of specific subunit assemblies in AMPA receptors is still poorly understood. The oligomerization is initiated by formation of dimers between N-terminal domains (NTD) 5 of nascent receptor polypeptides in the endoplasmic reticulum (ER) followed by interactions involving the transmembrane segments and the ligand binding domains (LBD) (9 -11). The relative strength of NTD contacts can partly explain the strong prefe...

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The N-terminal Domain Modulates α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) Receptor Desensitization

Cited by 26 publications

References 67 publications

Structure and Dynamics of AMPA Receptor GluA2 in Resting, Pre-Open, and Desensitized States

Structure and Dynamics of AMPA Receptor GluA2 in Resting, Pre-Open, and Desensitized States

Emerging structural insights into the function of ionotropic glutamate receptors

Aggregation Limits Surface Expression of Homomeric GluA3 Receptors

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