A modern ionotropic glutamate receptor with a K+ selectivity signature sequence

Janovjak, Harald; Sandoz, Guillaume; Isacoff, Ehud Y.

doi:10.1038/ncomms1231

Cited by 34 publications

(39 citation statements)

References 27 publications

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“…Our results, as well as recent work on AvGluR1 from the bilaterian rotifer Adineta vaga, which is activated by a range of hydrophobic amino acids as well as glutamate (42,52), as well as studies on Drosophila NMJ iGluRs that bind glutamate but not AMPA or kainate or NMDA (43), in addition to earlier work on GluR0 from the photosynthetic cyanobacterium Synechocystis sp PCC6803 and its homologs, which bind glutamate, glutamine, and serine but not glycine (53)(54)(55), illustrate that it is currently challenging to identify ligand selectivity for iGluRs either by sequence analysis or by analysis of phylogenetic trees based on iGluR LBD crystal structures (Fig. 1C).…”

Section: Discussionmentioning

confidence: 73%

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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Section: Discussionmentioning

confidence: 73%

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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“…3A, right lane). Given the homology between the TM region of iGluRs and K ϩ channels (8,32), which still tetramerize even in the absence of their specialized tetramerization domains (33)(34)(35), it is highly likely that the oligomer formed by HA-GluA1-⌬ECD/⌬CTD was also a tetramer. To probe the stoichiometry of this oligomer, we included 0.11% SDS in the solubilization buffer to disrupt inter-subunit interactions (see "Experimental Procedures" and the next section under "Results").…”

Section: Surface Trafficking Membrane Topology and Packing Of Pore-mentioning

confidence: 99%

The Transmembrane Domain Mediates Tetramerization of α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptors

Gan¹,

Dai

Zhou

et al. 2016

Journal of Biological Chemistry

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AMPA receptors (AMPARs) mediate fast excitatory neurotransmission in the central nervous system. Functional AMPARs are tetrameric complexes with a highly modular structure, consisting of four evolutionarily distinct structural domains: an amino-terminal domain (ATD), a ligand-binding domain (LBD), a channel-forming transmembrane domain (TMD), and a carboxyl-terminal domain (CTD). Here we show that the isolated TMD of the GluA1 AMPAR is fully capable of tetramerization. Additionally, removal of the extracellular domains from the receptor did not affect membrane topology or surface delivery. Furthermore, whereas the ATD and CTD contribute positively to tetramerization, the LBD presents a barrier to the process by reducing the stability of the receptor complex. These experiments pinpoint the TMD as the "tetramerization domain" for AMPARs, with other domains playing modulatory roles. They also raise intriguing questions about the evolution of iGluRs as well as the mechanisms regulating the biogenesis of AMPAR complexes.

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“…They can be transplanted between subunits or expressed in isolation while retaining functionality (such as ligand binding). Interestingly, prokaryotes appear to express "simplified" versions of iGluRs, lacking both the NTDs and CTDs but with a functional gating core machinery (ABDs þ TMD) (Chen et al 1999;Janovjak et al 2011).…”

Section: Modular Architecturementioning

confidence: 99%

Synaptic Neurotransmitter-Gated Receptors

Smart

Paoletti

2012

Cold Spring Harbor Perspectives in Biology

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Since the discovery of the major excitatory and inhibitory neurotransmitters and their receptors in the brain, many have deliberated over their likely structures and how these may relate to function. This was initially satisfied by the determination of the first amino acid sequences of the Cys-loop receptors that recognized acetylcholine, serotonin, GABA, and glycine, followed later by similar determinations for the glutamate receptors, comprising non-NMDA and NMDA subtypes. The last decade has seen a rapid advance resulting in the first structures of Cys-loop receptors, related bacterial and molluscan homologs, and glutamate receptors, determined down to atomic resolution. This now provides a basis for determining not just the complete structures of these important receptor classes, but also for understanding how various domains and residues interact during agonist binding, receptor activation, and channel opening, including allosteric modulation. This article reviews our current understanding of these mechanisms for the Cys-loop and glutamate receptor families.T o understand how neurons communicate with each other requires a fundamental understanding of neurotransmitter receptor structure and function. Neurotransmitter-gated ion channels, also known as ionotropic receptors, are responsible for fast synaptic transmission. They decode chemical signals into electrical responses, thereby transmitting information from one neuron to another. Their suitability for this important task relies on their ability to respond very rapidly to the transient release of neurotransmitter to affect cell excitability.In the central nervous system (CNS), fast synaptic transmission results in two main effects: neuronal excitation and inhibition. For excitation, the principal neurotransmitter involved is glutamate, which interacts with ionotropic (integral ion channel) and metabotropic (secondmessenger signaling) receptors. The ionotropic glutamate receptors are permeable to cations, which directly cause excitation. Acetylcholine and serotonin can also activate specific cationselective ionotropic receptors to affect neuronal excitation. For controlling cell excitability, inhibition is important, and this is mediated by the neurotransmitters GABA and glycine, causing an increased flux of anions. GABA predominates as the major inhibitory transmitter throughout

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A modern ionotropic glutamate receptor with a K+ selectivity signature sequence

Cited by 34 publications

References 27 publications

Glycine activated ion channel subunits encoded by ctenophore glutamate receptor genes

Glycine activated ion channel subunits encoded by ctenophore glutamate receptor genes

The Transmembrane Domain Mediates Tetramerization of α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptors

Synaptic Neurotransmitter-Gated Receptors

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