Crystal structure of a heterotetrameric NMDA receptor ion channel

Karakaş, Erkan; Furukawa, Hiro

doi:10.1126/science.1251915

Cited by 535 publications

(740 citation statements)

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“…This conclusion is also consistent with structural data showing that the LBD of GluA2 contains a number of zinc binding sites formed mainly by histidine residues (42). Because the ATD and LBD are tightly packed in NMDARs but more separated in AMPARs, with the consequence that the ATD is not a regulatory site for AMPARs (8,9), we propose that the LBD is a more likely site for allosteric AMPAR modulation by zinc. More studies are needed for determining the subunit sensitivity, the binding site, and the underlying biophysical mechanism of zinc-mediated AMPAR inhibition.…”

Section: Discussionsupporting

confidence: 78%

“…6 and 7]. Recent structural studies revealed that the amino terminal domain (ATD) and ligand-binding domain (LBD) are tightly packed in NMDARs but not AMPARs (8)(9)(10). These structural differences explain some of the functional differences in allosteric modulation between AMPARs and NMDARs, such as why the ATD of NMDARs, unlike that of AMPARs, modulates function and contains numerous binding sites for allosteric regulators.…”

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confidence: 99%

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AMPA receptor inhibition by synaptically released zinc

Kalappa

Anderson

Goldberg

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

111

149

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The vast amount of fast excitatory neurotransmission in the mammalian central nervous system is mediated by AMPA-subtype glutamate receptors (AMPARs). As a result, AMPAR-mediated synaptic transmission is implicated in nearly all aspects of brain development, function, and plasticity. Despite the central role of AMPARs in neurobiology, the fine-tuning of synaptic AMPA responses by endogenous modulators remains poorly understood. Here we provide evidence that endogenous zinc, released by single presynaptic action potentials, inhibits synaptic AMPA currents in the dorsal cochlear nucleus (DCN) and hippocampus. Exposure to loud sound reduces presynaptic zinc levels in the DCN and abolishes zinc inhibition, implicating zinc in experience-dependent AMPAR synaptic plasticity. Our results establish zinc as an activity-dependent, endogenous modulator of AMPARs that tunes fast excitatory neurotransmission and plasticity in glutamatergic synapses.AMPA receptors | zinc | ZnT3 | synaptic plasticity | auditory T he development, function, and experience-dependent plasticity of the mammalian brain depend on the refined neuronal interactions that occur in synapses. In the majority of excitatory synapses, the release of the neurotransmitter glutamate from presynaptic neurons opens transmembrane ion channels in postsynaptic neurons, the ionotropic glutamate receptors, thereby generating the flow of excitatory signaling in the brain. As a result, these receptors play a fundamental role in normal function and development of the brain, and they are also involved in many brain disorders (1).The ionotropic glutamate receptor family consists of AMPA, kainate, and NMDA receptors (NMDARs). Although kainate receptor-mediated excitatory postsynaptic responses occur in a few central synapses (2), AMPA receptors (AMPARs) and NMDARs are localized in the postsynaptic density of the vast majority of glutamatergic synapses in the brain, mediating most of excitatory neurotransmission (1). NMDAR function is regulated by a wide spectrum of endogenous allosteric neuromodulators that fine-tune synaptic responses (3-5); however, much less is known about endogenous AMPAR neuromodulators [(1, 5), but see refs. 6 and 7]. Recent structural studies revealed that the amino terminal domain (ATD) and ligand-binding domain (LBD) are tightly packed in NMDARs but not AMPARs (8-10). These structural differences explain some of the functional differences in allosteric modulation between AMPARs and NMDARs, such as why the ATD of NMDARs, unlike that of AMPARs, modulates function and contains numerous binding sites for allosteric regulators. Nonetheless, given the importance of fine-tuning both synaptic AMPAR and NMDAR responses for brain function, it is puzzling that there is not much evidence for endogenous, extracellular AMPAR modulation. The discovery and establishment of endogenous AMPAR modulators is crucial both for understanding ionotropic glutamate receptor signaling and for developing therapeutic agents for the treatment of AMPAR-related disorders, such as d...

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Section: Discussionsupporting

confidence: 78%

mentioning

confidence: 99%

AMPA receptor inhibition by synaptically released zinc

Kalappa

Anderson

Goldberg

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

111

149

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“…S2). Because the assembly of iGluR heterotetramers is mediated via a dimer of dimers organization (25,26,42) and coexpression of GluRIIA/E and Neto β induced small but significant currents, we speculate that the order of subunit arrangement in the Drosophila NMJ heterotetramers entails the formation of GluRIIA/E and the reciprocal C/D dimers. In Xenopus oocytes, surface expression of iGluR heterotetramers is much lower than that of vertebrate GluK2 (Fig.…”

Section: Discussionmentioning

confidence: 96%

“…3A), a position that in vertebrate GluA2 and GluK2 AMPA and kainate receptors is converted to an arginine by RNA editing (20)(21)(22). In the M3 helix, which forms the entrance to the ion channel pore in glutamate receptors (23)(24)(25)(26), Drosophila GluRIIB has three amino acid substitutions; most notable is the replacement of asparagine by lysine at position 647 (Fig. 3A).…”

Section: Efficient Receptor Expression and Function Requires Multiplementioning

confidence: 99%

Functional reconstitution ofDrosophila melanogasterNMJ glutamate receptors

Han

Dharkar

Mayer

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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The Drosophila larval neuromuscular junction (NMJ), at which glutamate acts as the excitatory neurotransmitter, is a widely used model for genetic analysis of synapse function and development. Despite decades of study, the inability to reconstitute NMJ glutamate receptor function using heterologous expression systems has complicated the analysis of receptor function, such that it is difficult to resolve the molecular basis for compound phenotypes observed in mutant flies. We find that Drosophila Neto functions as an essential component required for the function of NMJ glutamate receptors, permitting analysis of glutamate receptor responses in Xenopus oocytes. In combination with a crystallographic analysis of the GluRIIB ligand binding domain, we use this system to characterize the subunit dependence of assembly, channel block, and ligand selectivity for Drosophila NMJ glutamate receptors.T he amino acid L-glutamate is the major neurotransmitter at vertebrate excitatory central synapses and at the neuromuscular junction (NMJ) of insects and crustaceans (1-3). Many vertebrate AMPA and kainate receptors, as well as GluRI from the worm Caenorhabditis elegans and AvGluR1 from the rotifer Adineta vaga, can form functional homomeric ion channels (1, 4, 5). In contrast, genetic studies suggest that assembly of Drosophila NMJ type A and type B glutamate receptors requires four subunits: either GluRIIA or GluRIIB, plus GluRIIC, GluRIID, and GluRIIE (6-9); both subtypes desensitize rapidly, with time constants of 18.8 and 2.0 ms, respectively (6). In flies, lack of GluRIIA and GluRIIB or any other single subunit induces embryonic paralysis. Furthermore, in the absence of GluRIIA and GluRIIB, or any other subunit, none of the remaining iGluR subunits cluster at nascent synapses, suggesting that recruitment and stabilization of iGluRs at synaptic sites requires heterotetramers. Despite a decade of work, the molecular basis for this unique profile has remained obscure. In part, this is because the reconstitution of functional glutamate receptors (iGluRs) in heterologous systems, which has been a powerful tool for analysis of receptor function in other species, has not been achieved for the Drosophila NMJ (10).We recently demonstrated that the synaptic distribution of Drosophila NMJ iGluRs requires Neto (Neuropillin and Tolloidlike), a protein essential for NMJ function (11). Neto belongs to a family of highly conserved auxiliary proteins that modulate the function of vertebrate kainate receptors (12) and C. elegans AMPA receptors (13,14). In these species Neto plays a minor role in delivery and synaptic targeting, and instead modulates receptor gating properties. In contrast, in flies Neto is absolutely required for clustering of iGluRs at the NMJ and lack of Neto induces embryonic paralysis (11). This finding may reflect a role for Neto in receptor assembly, surface expression, synaptic trafficking and stabilization, or modulation of iGluR gating. To distinguish among these possibilities, a recombinant expression system for...

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“…Recently, two independent studies, by Karakas and Furukawa [4] and Lee et al [5], revealed the first insight of the crystal structure of NMDA receptor in almost complete configurations. In both studies, the NMDA receptors are heterotetrameric complexes comprised of two GluN1 and two GluN2B subunits.…”

Section: Editorialmentioning

confidence: 99%

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Crystal structure of a heterotetrameric NMDA receptor ion channel

Cited by 535 publications

References 44 publications

AMPA receptor inhibition by synaptically released zinc

AMPA receptor inhibition by synaptically released zinc

Functional reconstitution ofDrosophila melanogasterNMJ glutamate receptors

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