The Experts below are selected from a list of 33696 Experts worldwide ranked by ideXlab platform
David S Bredt - One of the best experts on this subject based on the ideXlab platform.
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transmembrane AMPA receptor regulatory proteins and cornichon 2 allosterically regulate AMPA receptor antagonists and potentiators
Journal of Biological Chemistry, 2011Co-Authors: Douglas A Schober, Douglas Linn Gernert, Matthew W Jeffries, Martin B. Gill, Akihiko Kato, Paul L. Ornstein, Hong Yu, Christian C Felder, David S BredtAbstract:Abstract AMPA receptors mediate fast excitatory transmission in the brain. Neuronal AMPA receptors comprise GluA pore-forming principal subunits and can associate with multiple modulatory components, including transmembrane AMPA receptor regulatory proteins (TARPs) and CNIHs (cornichons). AMPA receptor potentiators and non-competitive antagonists represent potential targets for a variety of neuropsychiatric disorders. Previous studies showed that the AMPA receptor antagonist GYKI-53655 displaces binding of a potentiator from brain receptors but not from recombinant GluA subunits. Here, we asked whether AMPA receptor modulatory subunits might resolve this discrepancy. We find that the cerebellar TARP, stargazin (γ-2), enhances the binding affinity of the AMPA receptor potentiator [3H]-LY450295 and confers sensitivity to displacement by non-competitive antagonists. In cerebellar membranes from stargazer mice, [3H]-LY450295 binding is reduced and relatively resistant to displacement by non-competitive antagonists. Coexpression of AMPA receptors with CNIH-2, which is expressed in the hippocampus and at low levels in the cerebellar Purkinje neurons, confers partial sensitivity of [3H]-LY450295 potentiator binding to displacement by non-competitive antagonists. Autoradiography of [3H]-LY450295 binding to stargazer and γ-8-deficient mouse brain sections, demonstrates that TARPs regulate the pharmacology of allosteric AMPA potentiators and antagonists in the cerebellum and hippocampus, respectively. These studies demonstrate that accessory proteins define AMPA receptor pharmacology by functionally linking allosteric AMPA receptor potentiator and antagonist sites.
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AMPA receptors and stargazin like transmembrane AMPA receptor regulatory proteins mediate hippocAMPAl kainate neurotoxicity
Proceedings of the National Academy of Sciences of the United States of America, 2007Co-Authors: Susumu Tomita, Roger A. Nicoll, Nathalie Rouach, Keith R Byrd, Camilla Bellone, Angela Venegas, Jessica L Obrien, Kwang S Kim, Olav Olsen, David S BredtAbstract:Naturally occurring glutamate analogs, such as kainate and domoate, which cause excitotoxic shellfish poisoning, induce nondesensitizing responses at neuronal α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. In addition to acting on AMPA receptors, kainate and domoate also activate high-affinity kainate-type glutamate receptors. The receptor type that mediates their neurotoxicity remains uncertain. Here, we show that the transmembrane AMPA receptor-associated protein (TARP) γ-2 (or stargazin) and the related TARP γ-8 augment responses to kainate and domoate by making these neurotoxins more potent and more efficacious AMPA receptor agonists. Genetic deletion of hippocAMPAl enriched γ-8 selectively abolishes sustained depolarizations in hippocampus mediated by kainate activation of AMPA receptors. γ-8 knockout mice display typical kainate-induced seizures; however, the associated neuronal cell death in the hippocampus is attenuated in mice lacking γ-8. This work decisively demonstrates that TARP-associated AMPA receptors mediate kainate neurotoxicity and identifies TARPs as targets for modulating neurotoxic properties of AMPA receptors.
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new transmembrane AMPA receptor regulatory protein isoform γ 7 differentially regulates AMPA receptors
The Journal of Neuroscience, 2007Co-Authors: Akihiko Kato, Eric S. Nisenbaum, Roger A. Nicoll, Wei Zhou, Aaron D Milstein, Mike D Knierman, Edward R Siuda, Joe E Dotzlaf, John E Hale, David S BredtAbstract: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, γ-2 (or stargazin), γ-3, γ-4, and γ-8, that control AMPA receptor trafficking, gating, and pharmacology. Here, we explore roles for the homologous γ-5 and γ-7 proteins, which were previously suggested not to serve as TARPs. Western blotting reveals high levels of γ-5 and γ-7 in the cerebellum, where γ-7 is enriched in Purkinje neurons in the molecular layer and glomerular synapses in the granule cell layer. Immunoprecipitation proteomics shows that cerebellar γ-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, γ-7 occurs together with PSD-95 and AMPA receptor subunits in purified postsynaptic densities. In heterologous cells, γ-7 but not γ-5 greatly enhances AMPA receptor glutamate-evoked currents and modulates channel gating. In granule cells from stargazer mice, transfection of γ-7 but not γ-5 increases AMPA receptor-mediated currents. Compared with stargazin, γ-7 differentially modulates AMPA receptor glutamate affinity and kainate efficacy. These studies define γ-7 as a new member of the TARP family that can differentially influence AMPA receptors in cerebellar neurons.
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synapse specific and developmentally regulated targeting of AMPA receptors by a family of maguk scaffolding proteins
Neuron, 2006Co-Authors: Guillermo M Elias, David S Bredt, Lars Funke, Valentin Stein, Seth G N Grant, Roger A. NicollAbstract:Trafficking of AMPA receptors (AMPA-Rs) to and from synapses controls the strength of excitatory synaptic transmission. However, proteins that cluster AMPA-Rs at synapses remain poorly understood. Here we show that PSD-95-like membrane-associated guanylate kinases (PSD-MAGUKs) mediate this synaptic targeting, and we uncover a remarkable functional redundancy within this protein family. By manipulating endogenous neuronal PSD-MAGUK levels, we find that both PSD-95 and PSD-93 independently mediate AMPA-R targeting at mature synapses. We also reveal unanticipated synapse heterogeneity as loss of either PSD-95 or PSD-93 silences largely nonoverlapping populations of excitatory synapses. In adult PSD-95 and PSD-93 double knockout animals, SAP-102 is upregulated and compensates for the loss of synaptic AMPA-Rs. At immature synapses, PSD-95 and PSD-93 play little role in synaptic AMPA-R clustering; instead, SAP-102 dominates. These studies establish a PSD-MAGUK-specific regulation of AMPA-R synaptic expression that establishes and maintains glutamatergic synaptic transmission in the mammalian central nervous system.
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tarp gamma 8 controls hippocAMPAl AMPA receptor number distribution and synaptic plasticity
Nature Neuroscience, 2005Co-Authors: Nathalie Rouach, David S Bredt, Susumu Tomita, Ronald S Petralia, Keith Byrd, Guillermo M Elias, Hillel Adesnik, Siavash Karimzadegan, Colin Kealey, Roger A. NicollAbstract:Synaptic plasticity involves activity-dependent trafficking of AMPA-type glutamate receptors. Numerous cytoplasmic scaffolding proteins are postulated to control AMPA receptor trafficking, but the detailed mechanisms remain unclear. Here, we show that the transmembrane AMPA receptor regulatory protein (TARP) γ-8, which is preferentially expressed in the mouse hippocampus, is important for AMPA receptor protein levels and extrasynaptic surface expression. By controlling the number of AMPA receptors, γ-8 is also important in long-term potentiation, but not long-term depression. This study establishes γ-8 as a critical protein for basal AMPA receptor expression and localization at extrasynaptic sites in the hippocampus and raises the possibility that TARP-dependent control of AMPA receptors during synapse development and plasticity may be widespread.
Paul L. Ornstein - One of the best experts on this subject based on the ideXlab platform.
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Discovery of the First α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptor Antagonist Dependent upon Transmembrane AMPA Receptor Regulatory Protein (TARP) γ-8
Journal of Medicinal Chemistry, 2016Co-Authors: Kevin Matthew Gardinier, Douglas Linn Gernert, Warren J. Porter, Jon K. Reel, Patrick Gianpietro Spinazze, F. Craig Stevens, Patric James Hahn, Sean P. Hollinshead, Paul L. Ornstein, Daniel Ray MayhughAbstract:Transmembrane AMPA receptor regulatory proteins (TARPs) are a family of scaffolding proteins that regulate AMPA receptor trafficking and function. TARP γ-8 is one member of this family and is highly expressed within the hippocampus relative to the cerebellum. A selective TARP γ-8-dependent AMPA receptor antagonist (TDAA) is an innovative approach to modulate AMPA receptors in specific brain regions to potentially increase the therapeutic index relative to known non-TARP-dependent AMPA antagonists. We describe here, for the first time, the discovery of a noncompetitive AMPA receptor antagonist that is dependent on the presence of TARP γ-8. Three major iteration cycles were employed to improve upon potency, CYP1A2-dependent challenges, and in vivo clearance. An optimized molecule, compound (−)-25 (LY3130481), was fully protective against pentylenetetrazole-induced convulsions in rats without the motor impairment associated with non-TARP-dependent AMPA receptor antagonists. Compound (−)-25 could be utilized ...
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transmembrane AMPA receptor regulatory proteins and cornichon 2 allosterically regulate AMPA receptor antagonists and potentiators
Journal of Biological Chemistry, 2011Co-Authors: Douglas A Schober, Douglas Linn Gernert, Matthew W Jeffries, Martin B. Gill, Akihiko Kato, Paul L. Ornstein, Hong Yu, Christian C Felder, David S BredtAbstract:Abstract AMPA receptors mediate fast excitatory transmission in the brain. Neuronal AMPA receptors comprise GluA pore-forming principal subunits and can associate with multiple modulatory components, including transmembrane AMPA receptor regulatory proteins (TARPs) and CNIHs (cornichons). AMPA receptor potentiators and non-competitive antagonists represent potential targets for a variety of neuropsychiatric disorders. Previous studies showed that the AMPA receptor antagonist GYKI-53655 displaces binding of a potentiator from brain receptors but not from recombinant GluA subunits. Here, we asked whether AMPA receptor modulatory subunits might resolve this discrepancy. We find that the cerebellar TARP, stargazin (γ-2), enhances the binding affinity of the AMPA receptor potentiator [3H]-LY450295 and confers sensitivity to displacement by non-competitive antagonists. In cerebellar membranes from stargazer mice, [3H]-LY450295 binding is reduced and relatively resistant to displacement by non-competitive antagonists. Coexpression of AMPA receptors with CNIH-2, which is expressed in the hippocampus and at low levels in the cerebellar Purkinje neurons, confers partial sensitivity of [3H]-LY450295 potentiator binding to displacement by non-competitive antagonists. Autoradiography of [3H]-LY450295 binding to stargazer and γ-8-deficient mouse brain sections, demonstrates that TARPs regulate the pharmacology of allosteric AMPA potentiators and antagonists in the cerebellum and hippocampus, respectively. These studies demonstrate that accessory proteins define AMPA receptor pharmacology by functionally linking allosteric AMPA receptor potentiator and antagonist sites.
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cyclothiazide acts at a site on the alpha amino 3 hydroxy 5 methyl 4 isoxazole propionic acid receptor complex that does not recognize competitive or noncompetitive AMPA receptor antagonists
Journal of Pharmacology and Experimental Therapeutics, 1995Co-Authors: M A Desai, J P Burnett, Paul L. OrnsteinAbstract:Activation of the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) subtype of ionotropic glutamate receptors by certain agonists, including AMPA and glutamate, has been shown to result in a rapid desensitization of the receptor. This desensitization is profoundly inhibited by the benzothiadiazide diuretic, cyclothiazide. We previously reported that cyclothiazide potentiates AMPA-induced [3H]norepinephrine ([3H]NE) release from rat hippocAMPAl slices. We used this system to investigate the possible interaction of cyclothiazide with various AMPA receptor antagonists, including the competitive antagonist LY293558 and the 2,3-benzodiazepine noncompetitive antagonist GYKI 53655. Cyclothiazide significantly potentiated both AMPA- and KA-induced [3H]NE release from slices of the rat hippocampus. LY293558 and GYKI 53655 inhibited the potentiated and nonpotentiated AMPA- and KA-induced [3H]NE release in a concentration-dependent manner. The IC50 values for inhibition of AMPA- or KA-induced [3H]NE release by either antagonist were not affected by the presence of cyclothiazide. Thus, cyclothiazide seems to interact at a site on the AMPA receptor complex which differs from either the glutamate recognition site or the 2,3-benzodiazepine allosteric site.
Richard L Huganir - One of the best experts on this subject based on the ideXlab platform.
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proteomic analysis of α amino 3 hydroxy 5 methyl 4 isoxazole propionate receptor complexes
Journal of Biological Chemistry, 2012Co-Authors: Mutsuo Nuriya, Myounggoo Kang, Kevin D Martindale, Richard L HuganirAbstract:Abstract The AMPA receptor (AMPA-R) is a major excitatory neurotransmitter receptor in the brain. Identifying and characterizing the neuronal proteins interacting with AMPA-Rs have provided important information about the molecular mechanisms underlying synaptic transmission and plasticity. In this study, to identify more AMPA-R interactors in vivo, we performed proteomic analyses of AMPA-R complexes from the brain. AMPA-R complexes were isolated from the brain through various combinations of biochemical techniques for solubilization, enrichment, and immunoprecipitation. Mass spectrometry analyses of these isolated complexes identified several novel components of the AMPA-R complexes as well as some previously identified components. The identification of these novel components helps to further define the complex mechanisms involved in the regulation of AMPA receptor function and synaptic plasticity.
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grip1 and 2 regulate activity dependent AMPA receptor recycling via exocyst complex interactions
Proceedings of the National Academy of Sciences of the United States of America, 2010Co-Authors: Lifang Mao, Kogo Takamiya, Gareth M Thomas, Da Ting Lin, Richard L HuganirAbstract:PSD-95/SAP90/DLG/ZO-1 (PDZ) domain-mediated protein–protein interactions play important roles in regulating AMPA receptor trafficking and neuronal plasticity. GRIP1 and GRIP2 are homologous multi-PDZ domain-containing proteins that bind to the C-termini of AMPA-R GluA2 and GluA3 subunits. Previous attempts to determine the cellular roles of GRIP1 and GRIP2 in neurons have been complicated by nonspecific reagents, and by the embryonic lethality of conventional GRIP1 KO mice. To circumvent these issues we developed a conditional targeted deletion strategy to knock out GRIP1 in postnatal neurons derived from GRIP2 KO mice. Loss of GRIP1 and 2 did not affect normal AMPA-R steady-state trafficking and endocytosis, but strikingly impaired activity-dependent AMPA-R recycling. This previously uncharacterized role for GRIP1 appears to be mediated by novel interactions with the cellular trafficking machinery via the exocyst protein complex. Indeed, disruption of GRIP1-exocyst binding caused a strikingly similar deficit in AMPA-R recycling. Together these findings reveal a previously unidentified role for AMPA-R-GRIP1-exocyst protein complexes in activity-dependent AMPA-R trafficking.
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differential regulation of AMPA receptor subunit trafficking by palmitoylation of two distinct sites
Neuron, 2005Co-Authors: Takashi Hayashi, Gavin Rumbaugh, Richard L HuganirAbstract:Modification of AMPA receptor function is a major mechanism for the regulation of synaptic transmission and underlies several forms of synaptic plasticity. Post-translational palmitoylation is a reversible modification that regulates localization of many proteins. Here, we report that palmitoylation of the AMPA receptor regulates receptor trafficking. All AMPA receptor subunits are palmitoylated on two cysteine residues in their transmembrane domain (TMD) 2 and in their C-terminal region. Palmitoylation on TMD 2 is upregulated by the palmitoyl acyl transferase GODZ and leads to an accumulation of the receptor in the Golgi and a reduction of receptor surface expression. C-terminal palmitoylation decreases interaction of the AMPA receptor with the 4.1N protein and regulates AMPA- and NMDA-induced AMPA receptor internalization. Moreover, depalmitoylation of the receptor is regulated by activation of glutamate receptors. These data suggest that regulated palmitoylation of AMPA receptor subunits modulates receptor trafficking and may be important for synaptic plasticity.
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grip a synaptic pdz domain containing protein that interacts with AMPA receptors
Nature, 1997Co-Authors: Hualing Dong, Richard Obrien, Eric T Fung, Anthony Lanahan, Paul F Worley, Richard L HuganirAbstract:AMPA glutamate receptors mediate the majority of rapid excitatory synaptic transmission in the central nervous system1,2 and play a role in the synaptic plasticity underlying learning and memory3,4. AMPA receptors are heteromeric complexes of four homologous subunits (GluRl–4) that differentially combine to form a variety of AMPA receptor subtypes1,2. These subunits are thought to have a large extracellular amino-terminal domain, three transmembrane domains and an intracellular carboxy-terminal domain5. AMPA receptors are localized at excitatory synapses and are not found on adjacent inhibitory synapses enriched in GABAA receptors6. The targeting of neurotransmitter receptors, such as AMPA receptors, and ion channels to synapses is essential for efficient transmission7,8. A protein motif called a PDZ domain is important in the targeting of a variety of membrane proteins to cell–cell junctions including synapses8–10. Here we identify a synaptic PDZ domain-containing protein GRIP (glutamate receptor interacting protein) that specifically interacts with the C termini of AMPA receptors. GRIP is a new member of the PDZ domain-containing protein family which has seven PDZ domains and no catalytic domain. GRIP appears to serve as an adapter protein that links AMPA receptors to other proteins and may be critical for the clustering of AMPA receptors at excitatory synapses in the brain.
Roger A. Nicoll - One of the best experts on this subject based on the ideXlab platform.
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syndig1 promotes excitatory synaptogenesis independent of AMPA receptor trafficking and biophysical regulation
PLOS ONE, 2013Co-Authors: Kathryn L Lovero, Sabine M Blankenship, Yun Shi, Roger A. NicollAbstract:AMPA receptors–mediators of fast, excitatory transmission and synaptic plasticity in the brain–achieve great functional diversity through interaction with different auxiliary subunits, which alter both the trafficking and biophysical properties of these receptors. In the past several years an abundance of new AMPA receptor auxiliary subunits have been identified, adding astounding variety to the proteins known to directly bind and modulate AMPA receptors. SynDIG1 was recently identified as a novel AMPA receptor interacting protein that directly binds to the AMPA receptor subunit GluA2 in heterologous cells. Functionally, SynDIG1 was found to regulate the strength and density of AMPA receptor containing synapses in hippocAMPAl neurons, though the way in which SynDIG1 exerts these effects remains unknown. Here, we aimed to determine if SynDIG1 acts as a traditional auxiliary subunit, directly regulating the function and localization of AMPA receptors in the rat hippocampus. We find that, unlike any of the previously characterized AMPA receptor auxiliary subunits, SynDIG1 expression does not impact AMPA receptor gating, pharmacology, or surface trafficking. Rather, we show that SynDIG1 regulates the number of functional excitatory synapses, altering both AMPA and NMDA receptor mediated transmission. Our findings suggest that SynDIG1 is not a typical auxiliary subunit to AMPA receptors, but instead is a protein critical to excitatory synaptogenesis.
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AMPA receptors and stargazin like transmembrane AMPA receptor regulatory proteins mediate hippocAMPAl kainate neurotoxicity
Proceedings of the National Academy of Sciences of the United States of America, 2007Co-Authors: Susumu Tomita, Roger A. Nicoll, Nathalie Rouach, Keith R Byrd, Camilla Bellone, Angela Venegas, Jessica L Obrien, Kwang S Kim, Olav Olsen, David S BredtAbstract:Naturally occurring glutamate analogs, such as kainate and domoate, which cause excitotoxic shellfish poisoning, induce nondesensitizing responses at neuronal α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. In addition to acting on AMPA receptors, kainate and domoate also activate high-affinity kainate-type glutamate receptors. The receptor type that mediates their neurotoxicity remains uncertain. Here, we show that the transmembrane AMPA receptor-associated protein (TARP) γ-2 (or stargazin) and the related TARP γ-8 augment responses to kainate and domoate by making these neurotoxins more potent and more efficacious AMPA receptor agonists. Genetic deletion of hippocAMPAl enriched γ-8 selectively abolishes sustained depolarizations in hippocampus mediated by kainate activation of AMPA receptors. γ-8 knockout mice display typical kainate-induced seizures; however, the associated neuronal cell death in the hippocampus is attenuated in mice lacking γ-8. This work decisively demonstrates that TARP-associated AMPA receptors mediate kainate neurotoxicity and identifies TARPs as targets for modulating neurotoxic properties of AMPA receptors.
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new transmembrane AMPA receptor regulatory protein isoform γ 7 differentially regulates AMPA receptors
The Journal of Neuroscience, 2007Co-Authors: Akihiko Kato, Eric S. Nisenbaum, Roger A. Nicoll, Wei Zhou, Aaron D Milstein, Mike D Knierman, Edward R Siuda, Joe E Dotzlaf, John E Hale, David S BredtAbstract: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, γ-2 (or stargazin), γ-3, γ-4, and γ-8, that control AMPA receptor trafficking, gating, and pharmacology. Here, we explore roles for the homologous γ-5 and γ-7 proteins, which were previously suggested not to serve as TARPs. Western blotting reveals high levels of γ-5 and γ-7 in the cerebellum, where γ-7 is enriched in Purkinje neurons in the molecular layer and glomerular synapses in the granule cell layer. Immunoprecipitation proteomics shows that cerebellar γ-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, γ-7 occurs together with PSD-95 and AMPA receptor subunits in purified postsynaptic densities. In heterologous cells, γ-7 but not γ-5 greatly enhances AMPA receptor glutamate-evoked currents and modulates channel gating. In granule cells from stargazer mice, transfection of γ-7 but not γ-5 increases AMPA receptor-mediated currents. Compared with stargazin, γ-7 differentially modulates AMPA receptor glutamate affinity and kainate efficacy. These studies define γ-7 as a new member of the TARP family that can differentially influence AMPA receptors in cerebellar neurons.
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synapse specific and developmentally regulated targeting of AMPA receptors by a family of maguk scaffolding proteins
Neuron, 2006Co-Authors: Guillermo M Elias, David S Bredt, Lars Funke, Valentin Stein, Seth G N Grant, Roger A. NicollAbstract:Trafficking of AMPA receptors (AMPA-Rs) to and from synapses controls the strength of excitatory synaptic transmission. However, proteins that cluster AMPA-Rs at synapses remain poorly understood. Here we show that PSD-95-like membrane-associated guanylate kinases (PSD-MAGUKs) mediate this synaptic targeting, and we uncover a remarkable functional redundancy within this protein family. By manipulating endogenous neuronal PSD-MAGUK levels, we find that both PSD-95 and PSD-93 independently mediate AMPA-R targeting at mature synapses. We also reveal unanticipated synapse heterogeneity as loss of either PSD-95 or PSD-93 silences largely nonoverlapping populations of excitatory synapses. In adult PSD-95 and PSD-93 double knockout animals, SAP-102 is upregulated and compensates for the loss of synaptic AMPA-Rs. At immature synapses, PSD-95 and PSD-93 play little role in synaptic AMPA-R clustering; instead, SAP-102 dominates. These studies establish a PSD-MAGUK-specific regulation of AMPA-R synaptic expression that establishes and maintains glutamatergic synaptic transmission in the mammalian central nervous system.
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tarp gamma 8 controls hippocAMPAl AMPA receptor number distribution and synaptic plasticity
Nature Neuroscience, 2005Co-Authors: Nathalie Rouach, David S Bredt, Susumu Tomita, Ronald S Petralia, Keith Byrd, Guillermo M Elias, Hillel Adesnik, Siavash Karimzadegan, Colin Kealey, Roger A. NicollAbstract:Synaptic plasticity involves activity-dependent trafficking of AMPA-type glutamate receptors. Numerous cytoplasmic scaffolding proteins are postulated to control AMPA receptor trafficking, but the detailed mechanisms remain unclear. Here, we show that the transmembrane AMPA receptor regulatory protein (TARP) γ-8, which is preferentially expressed in the mouse hippocampus, is important for AMPA receptor protein levels and extrasynaptic surface expression. By controlling the number of AMPA receptors, γ-8 is also important in long-term potentiation, but not long-term depression. This study establishes γ-8 as a critical protein for basal AMPA receptor expression and localization at extrasynaptic sites in the hippocampus and raises the possibility that TARP-dependent control of AMPA receptors during synapse development and plasticity may be widespread.
Susumu Tomita - One of the best experts on this subject based on the ideXlab platform.
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tarp phosphorylation regulates synaptic AMPA receptors through lipid bilayers
Neuron, 2010Co-Authors: Akio Sumioka, Dan Yan, Susumu TomitaAbstract:Neurons use neurotransmitters to communicate across synapses, constructing neural circuits in the brain. AMPA-type glutamate receptors are the predominant excitatory neurotransmitter receptors mediating fast synaptic transmission. AMPA receptors localize at synapses by forming protein complexes with transmembrane AMPA receptor regulatory proteins (TARPs) and PSD-95-like membrane-associated guanylate kinases. Among the three classes of ionotropic glutamate receptors (AMPA, NMDA, and kainate type), AMPA receptor activity is most regulatable by neuronal activity to adjust synaptic strength. Here, we mutated the prototypical TARP, stargazin, and found that TARP phosphorylation regulates synaptic AMPA receptor activity in vivo. We also found that stargazin interacts with negatively charged lipid bilayers in a phosphorylation-dependent manner and that the lipid interaction inhibited stargazin binding to PSD-95. Cationic lipids dissociated stargazin from lipid bilayers and enhanced synaptic AMPA receptor activity in a stargazin phosphorylation-dependent manner. Thus, TARP phosphorylation plays a critical role in regulating AMPA receptor-mediated synaptic transmission via a lipid bilayer interaction.
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AMPA receptors and stargazin like transmembrane AMPA receptor regulatory proteins mediate hippocAMPAl kainate neurotoxicity
Proceedings of the National Academy of Sciences of the United States of America, 2007Co-Authors: Susumu Tomita, Roger A. Nicoll, Nathalie Rouach, Keith R Byrd, Camilla Bellone, Angela Venegas, Jessica L Obrien, Kwang S Kim, Olav Olsen, David S BredtAbstract:Naturally occurring glutamate analogs, such as kainate and domoate, which cause excitotoxic shellfish poisoning, induce nondesensitizing responses at neuronal α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. In addition to acting on AMPA receptors, kainate and domoate also activate high-affinity kainate-type glutamate receptors. The receptor type that mediates their neurotoxicity remains uncertain. Here, we show that the transmembrane AMPA receptor-associated protein (TARP) γ-2 (or stargazin) and the related TARP γ-8 augment responses to kainate and domoate by making these neurotoxins more potent and more efficacious AMPA receptor agonists. Genetic deletion of hippocAMPAl enriched γ-8 selectively abolishes sustained depolarizations in hippocampus mediated by kainate activation of AMPA receptors. γ-8 knockout mice display typical kainate-induced seizures; however, the associated neuronal cell death in the hippocampus is attenuated in mice lacking γ-8. This work decisively demonstrates that TARP-associated AMPA receptors mediate kainate neurotoxicity and identifies TARPs as targets for modulating neurotoxic properties of AMPA receptors.
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tarp gamma 8 controls hippocAMPAl AMPA receptor number distribution and synaptic plasticity
Nature Neuroscience, 2005Co-Authors: Nathalie Rouach, David S Bredt, Susumu Tomita, Ronald S Petralia, Keith Byrd, Guillermo M Elias, Hillel Adesnik, Siavash Karimzadegan, Colin Kealey, Roger A. NicollAbstract:Synaptic plasticity involves activity-dependent trafficking of AMPA-type glutamate receptors. Numerous cytoplasmic scaffolding proteins are postulated to control AMPA receptor trafficking, but the detailed mechanisms remain unclear. Here, we show that the transmembrane AMPA receptor regulatory protein (TARP) γ-8, which is preferentially expressed in the mouse hippocampus, is important for AMPA receptor protein levels and extrasynaptic surface expression. By controlling the number of AMPA receptors, γ-8 is also important in long-term potentiation, but not long-term depression. This study establishes γ-8 as a critical protein for basal AMPA receptor expression and localization at extrasynaptic sites in the hippocampus and raises the possibility that TARP-dependent control of AMPA receptors during synapse development and plasticity may be widespread.
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functional studies and distribution define a family of transmembrane AMPA receptor regulatory proteins
Journal of Cell Biology, 2003Co-Authors: Susumu Tomita, Roger A. Nicoll, Lu Chen, Yoshimi Kawasaki, Ronald S Petralia, Robert J Wenthold, David S BredtAbstract:Functional expression of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in cerebellar granule cells requires stargazin, a member of a large family of four-pass transmembrane proteins. Here, we define a family of transmembrane AMPA receptor regulatory proteins (TARPs), which comprise stargazin, γ-3, γ-4, and γ-8, but not related proteins, that mediate surface expression of AMPA receptors. TARPs exhibit discrete and complementary patterns of expression in both neurons and glia in the developing and mature central nervous system. In brain regions that express multiple isoforms, such as cerebral cortex, TARP–AMPA receptor complexes are strictly segregated, suggesting distinct roles for TARP isoforms. TARPs interact with AMPA receptors at the postsynaptic density, and surface expression of mature AMPA receptors requires a TARP. These studies indicate a general role for TARPs in controlling synaptic AMPA receptors throughout the central nervous system.
