Subunit-selective N-terminal domain associations organize the formation of AMPA receptor heteromers

Rossmann, Maxim; Sukumaran, Madhav; Penn, Andrew C.; Veprintsev, Dmitry B.; Babu, M. Madan; Greger, Ingo H.

doi:10.1038/emboj.2011.16

Cited by 107 publications

(209 citation statements)

References 81 publications

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“…priority, supporting the notion that the ATDs are critical for the first step of heterodimerization (11,31,33).…”

Section: Discussionmentioning

confidence: 56%

“…Previous studies demonstrated that heterodimers could be formed both in isolated ATDs of GluA2 and GluA3 (39,40) and in kainate receptors (20,41). The velocity sedimentation study of isolated ATDs shows that the heterodimer of GluA1/A2 ATDs has the smallest dissociation constant (K d ); thus, the heterodimers are preferred (31). In our study, ATDs form heterodimers in the full-length GluA1/A2.…”

Section: Discussionmentioning

confidence: 73%

“…According to previous reports, ATDs could affect AMPAR assembly (11,(30)(31)(32)(33). To determine whether ATDs play a role in determining AMPAR spatial assembly, we made chimeric construct of GluA1-2 by linking GluA1 amino-terminal sequence (ATS; ATD plus SP) to the LBD of GluA2m, and GluA2-1 by fusing the ATS of GluA2 to the LBD of GluA1m.…”

Section: Glua1 and Glua2 Have Preferred Positions In Tetrameric Assemmentioning

confidence: 99%

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GluA1 signal peptide determines the spatial assembly of heteromeric AMPA receptors

Kalyanaraman

et al. 2016

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

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AMPA-type glutamate receptors (AMPARs) mediate fast excitatory neurotransmission and predominantly assemble as heterotetramers in the brain. Recently, the crystal structures of homotetrameric GluA2 demonstrated that AMPARs are assembled with two pairs of conformationally distinct subunits, in a dimer of dimers formation. However, the structure of heteromeric AMPARs remains unclear. Guided by the GluA2 structure, we performed cysteine mutant cross-linking experiments in fulllength GluA1/A2, aiming to draw the heteromeric AMPAR architecture. We found that the amino-terminal domains determine the first level of heterodimer formation. When the dimers further assemble into tetramers, GluA1 and GluA2 subunits have preferred positions, possessing a 1-2-1-2 spatial assembly. By swapping the critical sequences, we surprisingly found that the spatial assembly pattern is controlled by the excisable signal peptides. Replacements with an unrelated GluK2 signal peptide demonstrated that GluA1 signal peptide plays a critical role in determining the spatial priority. Our study thus uncovers the spatial assembly of an important type of glutamate receptors in the brain and reveals a novel function of signal peptides.AMPA receptors | signal peptide | spatial assembly | stoichiometry

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“…priority, supporting the notion that the ATDs are critical for the first step of heterodimerization (11,31,33).…”

Section: Discussionmentioning

confidence: 56%

Section: Discussionmentioning

confidence: 73%

Section: Glua1 and Glua2 Have Preferred Positions In Tetrameric Assemmentioning

confidence: 99%

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GluA1 signal peptide determines the spatial assembly of heteromeric AMPA receptors

Kalyanaraman

et al. 2016

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

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“…However, there is considerable flexibility in the NTD dimer interface that allows the formation of GluA2-lacking AMPARs when appropriate to the relevant physiological and pathological conditions. 75 . Most assembled AMPAR tetramers contain GluA2 9 and this is strongly regulated by Q/R editing of the GluA2 subunit.…”

Section: Rna Editing Ampar Assembly and Er Exitmentioning

confidence: 99%

Synaptic AMPA receptor composition in development, plasticity and disease

2016

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General rightsThis document is made available in accordance with publisher policies. Please cite only the published version using the reference above. PrefaceAMPARs are assemblies of four core subunits, GluA1-4, that mediate most fast excitatory neurotransmission. The component subunits determine the functional properties of AMPARs and the prevailing view is that the subunit composition also determines AMPAR trafficking, which is dynamically regulated during development, synaptic plasticity, and in response to neuronal stress in disease. Recently, the subunit-dependence of AMPAR trafficking has been questioned leading to a reappraisal of the field. Here we review what is known, uncertain, conjectured and unknown about the roles of individual subunits and how they impact on AMPAR assembly, trafficking and function under normal and pathological conditions. IntroductionAMPA receptors (AMPARs) are a subtype of ionotropic glutamate receptors that are the 'work-horses' of fast excitatory neurotransmission in the CNS. Developmentallyand activity-regulated changes in the numbers and properties of AMPARs localized at the postsynaptic membrane are essential for excitatory synapse formation, stabilization, synaptic plasticity and neural circuit formation. Consequently, the logistics of the delivery, retention and removal of individual AMPARs with defined subunit compositions at specific synapses is highly complex. A typical cortical or hippocampal pyramidal neuron contains on the order of 10,000 synapses and the AMPARs at each synapse are independently and dynamically regulated in response to developmental cues, synaptic activity and environmental stresses. Furthermore, defects in the processes that control AMPAR assembly, trafficking and synaptic expression are intimately linked to psychiatric and neurological conditions, and also with cognitive decline in neurodegenerative diseases. Remarkable progress has been achieved in understanding how AMPAR trafficking, is orchestrated by a large array of AMPAR interacting proteins. These studies have established a set of hierarchical subunit-specific rules that control AMPAR trafficking under basal and activity-dependent conditions. Furthermore, there has been a growing appreciation that subunit composition can tune the properties of AMPARs to specific conditions. Nonetheless, how AMPARs comprising different subunits are differentially trafficked to control synaptic development, stabilisation and plasticity is a key unanswered question. Here, we provide an overview of the current state of knowledge of subunit-specific AMPAR trafficking and outline what we believe to be the key unresolved questions in the field. 2 Subunit-specific traffickingMost AMPARs are heterotetrameric assemblies of combinations of the subunits GluA1, GluA2, GluA3 and GluA4. AMPARs are expressed in both neurons and glia throughout the CNS 1 and have a turnover time of between 10 hours and 2 days depending on the type of neuron and developmental stage 2,3 . Each subunit has an identical membrane topology and c...

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“…Previous studies have identified structural elements that contribute to the assembly of AMPARs in almost every domain (5,11,12). The ATD of AMPARs forms dimers in solution and drive the initial dimerization process (13)(14)(15). Alternative splicing in the LBD (flip/flop) influences subunit composition of AMPAR heteromers, potentially by affecting the tetramerization process (16).…”

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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Subunit-selective N-terminal domain associations organize the formation of AMPA receptor heteromers

Cited by 107 publications

References 81 publications

GluA1 signal peptide determines the spatial assembly of heteromeric AMPA receptors

GluA1 signal peptide determines the spatial assembly of heteromeric AMPA receptors

Synaptic AMPA receptor composition in development, plasticity and disease

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

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