Zinc Potentiates GluK3 Glutamate Receptor Function by Stabilizing the Ligand Binding Domain Dimer Interface

Veran, Julien; Kumar, Janesh; Pinheiro, Paulo S.; Athané, A.; Mayer, Mark L.; Perrais, David; Mulle, Christophe

doi:10.1016/j.neuron.2012.08.027

Cited by 55 publications

(94 citation statements)

References 57 publications

(114 reference statements)

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“…, and Zn 2+ ions in vertebrate glutamate receptors (28)(29)(30)(31)(32), Mg 2+ stabilizes the LBD dimer assembly in ctenophores. Endogenous glycine is trapped in the ligand binding site.…”

Section: Resultsmentioning

confidence: 99%

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Glycine activated ion channel subunits encoded by ctenophore glutamate receptor genes

Alberstein

Grey

Zimmet

et al. 2015

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

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Recent genome projects for ctenophores have revealed the presence of numerous ionotropic glutamate receptors (iGluRs) in Mnemiopsis leidyi and Pleurobrachia bachei, among our earliest metazoan ancestors. Sequence alignments and phylogenetic analysis show that these form a distinct clade from the well-characterized AMPA, kainate, and NMDA iGluR subtypes found in vertebrates. Although annotated as glutamate and kainate receptors, crystal structures of the ML032222a and PbiGluR3 ligand-binding domains (LBDs) reveal endogenous glycine in the binding pocket, whereas ligand-binding assays show that glycine binds with nanomolar affinity; biochemical assays and structural analysis establish that glutamate is occluded from the binding cavity. Further analysis reveals ctenophore-specific features, such as an interdomain Arg-Glu salt bridge, present only in subunits that bind glycine, but also a conserved disulfide in loop 1 of the LBD that is found in all vertebrate NMDA but not AMPA or kainate receptors. We hypothesize that ctenophore iGluRs are related to an early ancestor of NMDA receptors, suggesting a common evolutionary path for ctenophores and bilaterian species, and suggest that future work should consider both glycine and glutamate as candidate neurotransmitters in ctenophore species.NMDA receptors | ctenophores | crystal structures | evolution I n the nervous system and neuromuscular junction of many animal species, the amino acid L-glutamate acts as an excitatory neurotransmitter. The molecular organization of glutamate receptor ion channel (iGluR) subunits into an amino terminal domain (ATD), and a ligand binding domain (LBD) bisected by insertion of a pore loop ion channel generates a unique structural signature, distinct from that for other neurotransmitter receptors, that is easily identified by sequence analysis. Using this approach, hundreds of iGluR homologs are emerging from genome sequencing projects (1-5). Virtually all of these are glutamate receptors in name only; their functional properties, physiological function, and the ligands they bind have yet to be determined. Recent large-scale sequencing projects, which place ctenophores as candidates for the earliest metazoan lineage, reveal that iGluR homologs are abundantly represented in the genomes of the comb jelly Mnemiopsis leidyi and the sea gooseberry Pleurobrachia bachei, suggesting that glutamate was selected to act as a neurotransmitter very early in evolution (4, 5). The muscle cells of P. bachei respond to application of glutamate with action potential generation and both species have neural networks and exhibit complex predatory behaviors that might also be generated by iGluR activity (4, 5). However, as for most species studied in sequencing projects, ctenophore iGluRs have yet to be characterized.By contrast to our primitive state of knowledge for iGluRs recently discovered by genome sequencing projects, the iGluRs of vertebrate species have been extensively characterized, and based on their ligand binding properties, amino acid sequences...

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“…, and Zn 2+ ions in vertebrate glutamate receptors (28)(29)(30)(31)(32), Mg 2+ stabilizes the LBD dimer assembly in ctenophores. Endogenous glycine is trapped in the ligand binding site.…”

Section: Resultsmentioning

confidence: 99%

“…2A and Fig. S5 (31,32) and is generated by conserved amino acid substitutions unique to ctenophores (Fig. S6).…”

Section: Resultsmentioning

confidence: 99%

Glycine activated ion channel subunits encoded by ctenophore glutamate receptor genes

Alberstein

Grey

Zimmet

et al. 2015

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

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“…S6C). The cavity volume for GluRIIB is similar to that for GluA2 (218 Å 3 ), which binds both AMPA and kainate, as well as quisqualate (38,40), but smaller than that for GluK1, GluK2, and GluK3 volume 305, 255, and 299 Å 3 , respectively (39,41), suggesting that structural features unique to Drosophila NMJ iGluRs control ligand selectivity.…”

Section: Efficient Receptor Expression and Function Requires Multiplementioning

confidence: 92%

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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“…Since the surprising discovery that Zn 2+ is present in large amounts within synaptic vesicles in many areas of the brain (Maske, 1955), numerous studies have investigated the possible roles of this metal on synaptic function. These studies have revealed that synaptic Zn 2+ -- as an allosteric modulator -- inhibits GABA A , NMDA, and kainate receptors (Paoletti et al, 1997; Vogt et al, 2000; Ruiz et al, 2004; Mott et al, 2008; Nozaki et al, 2011; Veran et al, 2012), while potentiating glycine receptors (Hirzel et al, 2006). Moreover, synaptic Zn 2+ -- as a trigger of signaling pathways -- is thought to be required for mossy fiber long-term potentiation (LTP) via pre– and postsynaptic mechanisms (Huang et al, 2008; Pan et al, 2011); however, these results are not consistent with other studies suggesting that Zn 2+ signaling does not affect mossy fiber LTP (Vogt et al, 2000; Lavoie et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Synaptic Zn²⁺Inhibits Neurotransmitter Release by Promoting Endocannabinoid Synthesis

Perez‐Rosello¹,

Anderson²,

Schöpfer³

et al. 2013

J. Neurosci.

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Although it is well established that many glutamatergic neurons sequester Zn2+ within their synaptic vesicles, the physiological significance of synaptic Zn2+ remains poorly understood. In experiments performed in a Zn2+-enriched auditory brainstem nucleus -- the dorsal cochlear nucleus -- we discovered that synaptic Zn2+ and GPR39, a putative metabotropic Zn2+-sensing receptor (mZnR), are necessary for triggering the synthesis of the endocannabinoid 2-arachidonoylglycerol (2-AG). The postsynaptic production of 2-AG, in turn, inhibits presynaptic probability of neurotransmitter release, thus shaping synaptic strength and short-term synaptic plasticity. Zn2+-induced inhibition of transmitter release is absent in mutant mice that lack either vesicular Zn2+ or the mZnR. Moreover, mass spectrometry measurements of 2-AG levels reveal that Zn2+-mediated initiation of 2-AG synthesis is absent in mice lacking the mZnR. We reveal a previously unknown action of synaptic Zn2+: synaptic Zn2+ inhibits glutamate release by promoting 2-AG synthesis.

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Zinc Potentiates GluK3 Glutamate Receptor Function by Stabilizing the Ligand Binding Domain Dimer Interface

Cited by 55 publications

References 57 publications

Glycine activated ion channel subunits encoded by ctenophore glutamate receptor genes

Glycine activated ion channel subunits encoded by ctenophore glutamate receptor genes

Functional reconstitution ofDrosophila melanogasterNMJ glutamate receptors

Synaptic Zn²⁺Inhibits Neurotransmitter Release by Promoting Endocannabinoid Synthesis

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Zinc Potentiates GluK3 Glutamate Receptor Function by Stabilizing the Ligand Binding Domain Dimer Interface

Cited by 55 publications

References 57 publications

Glycine activated ion channel subunits encoded by ctenophore glutamate receptor genes

Glycine activated ion channel subunits encoded by ctenophore glutamate receptor genes

Functional reconstitution ofDrosophila melanogasterNMJ glutamate receptors

Synaptic Zn2+Inhibits Neurotransmitter Release by Promoting Endocannabinoid Synthesis

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Synaptic Zn²⁺Inhibits Neurotransmitter Release by Promoting Endocannabinoid Synthesis