Reconstitution of invertebrate glutamate receptor function depends on stargazin-like proteins

Walker, Colin; Brockie, Penelope J.; Madsen, David M.; Francis, Michael M.; Zheng, Yi; Koduri, Sri; Mellem, Jerry E.; Strutz‐Seebohm, Nathalie; Maricq, Andres V.

doi:10.1073/pnas.0604482103

Cited by 61 publications

(94 citation statements)

References 41 publications

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“…Recent studies have shown that stargazin-like molecules occur in worms and flies, and these proteins are critical for the activity of AMPA receptor gene products in these invertebrates (Walker et al, 2006). TARPs in all organisms selectively regulate AMPA-type GluRs and do not modulate other receptors or channels.…”

Section: Discussionmentioning

confidence: 99%

New Transmembrane AMPA Receptor Regulatory Protein Isoform, γ-7, Differentially Regulates AMPA Receptors

Kato¹,

Zhou²,

Milstein³

et al. 2007

J. Neurosci.

125

168

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AMPA-type glutamate receptors (GluRs) mediate most excitatory signaling in the brain and are composed of GluR principal subunits and transmembrane AMPA receptor regulatory protein (TARP) auxiliary subunits. Previous studies identified four mammalian TARPs, ␥-2 (or stargazin), ␥-3, ␥-4, and ␥-8, that control AMPA receptor trafficking, gating, and pharmacology. Here, we explore roles for the homologous ␥-5 and ␥-7 proteins, which were previously suggested not to serve as TARPs. Western blotting reveals high levels of ␥-5 and ␥-7 in the cerebellum, where ␥-7 is enriched in Purkinje neurons in the molecular layer and glomerular synapses in the granule cell layer. Immunoprecipitation proteomics shows that cerebellar ␥-7 avidly and selectively binds to AMPA receptor GluR subunits and also binds to the AMPA receptor clustering protein, postsynaptic density-95 (PSD-95). Furthermore, ␥-7 occurs together with PSD-95 and AMPA receptor subunits in purified postsynaptic densities. In heterologous cells, ␥-7 but not ␥-5 greatly enhances AMPA receptor glutamateevoked currents and modulates channel gating. In granule cells from stargazer mice, transfection of ␥-7 but not ␥-5 increases AMPA receptor-mediated currents. Compared with stargazin, ␥-7 differentially modulates AMPA receptor glutamate affinity and kainate efficacy. These studies define ␥-7 as a new member of the TARP family that can differentially influence AMPA receptors in cerebellar neurons.

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Section: Discussionmentioning

confidence: 99%

New Transmembrane AMPA Receptor Regulatory Protein Isoform, γ-7, Differentially Regulates AMPA Receptors

Kato¹,

Zhou²,

Milstein³

et al. 2007

J. Neurosci.

125

168

View full text Add to dashboard Cite

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“…4E, upper traces). This is not unexpected, as Caenorhabditis elegans and Drosophila melanogaster GluAs require coinjection of transmembrane GluA regulatory proteins (TARPs) to achieve a glutamate response (30)(31)(32). TARPs facilitate the membrane targeting and channel function of GluAs (33,34).…”

Section: Resultsmentioning

confidence: 99%

AMPA glutamate receptors are required for sensory-organ formation and morphogenesis in the basal chordate

Hirai

Hotta

Kubo

et al. 2017

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

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AMPA-type glutamate receptors (GluAs) mediate fast excitatory transmission in the vertebrate central nervous system (CNS), and their function has been extensively studied in the mature mammalian brain. However, GluA expression begins very early in developing embryos, suggesting that they may also have unidentified developmental roles. Here, we identify developmental roles for GluAs in the ascidian Ciona intestinalis. Mammals express Ca2+-permeable GluAs (Ca-P GluAs) and Ca2+-impermeable GluAs (Ca-I GluAs) by combining subunits derived from four genes. In contrast, ascidians have a single gluA gene. Taking advantage of the simple genomic GluA organization in ascidians, we knocked down (KD) GluAs in Ciona and observed severe impairments in formation of the ocellus, a photoreceptive organ used during the swimming stage, and in resorption of the tail and body axis rotation during metamorphosis to the adult stage. These defects could be rescued by injection of KD-resistant GluAs. GluA KD phenotypes could also be reproduced by expressing a GluA mutant that dominantly inhibits glutamate-evoked currents. These results suggest that, in addition to their role in synaptic communication in mature animals, GluAs also have critical developmental functions.

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“…This finding suggests that additional auxiliary subunits may aid in targeting the NMJ heterotetramers to the cell surface. Indeed, the Drosophila genome codes for Stargazinlike (Stg1) and two Cornichon-type proteins that may regulate the surface expression of NMJ receptors (4,43). Our results suggest that the function of Drosophila Neto is conserved with that in vertebrates and C. elegans: modulation of receptor function is the major role of Neto, with much less of an effect on surface delivery (12,13).…”

Section: Discussionmentioning

confidence: 99%

“…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).…”

mentioning

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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Reconstitution of invertebrate glutamate receptor function depends on stargazin-like proteins

Cited by 61 publications

References 41 publications

New Transmembrane AMPA Receptor Regulatory Protein Isoform, γ-7, Differentially Regulates AMPA Receptors

New Transmembrane AMPA Receptor Regulatory Protein Isoform, γ-7, Differentially Regulates AMPA Receptors

AMPA glutamate receptors are required for sensory-organ formation and morphogenesis in the basal chordate

Functional reconstitution ofDrosophila melanogasterNMJ glutamate receptors

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