AMPA Receptor Tetramerization Is Mediated by Q/R Editing

Greger, Ingo H.; Khatri, Latika; Kong, Xiang‐Peng; Ziff, Edward B.

doi:10.1016/s0896-6273(03)00668-8

Cited by 276 publications

(308 citation statements)

References 51 publications

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“…A few sitesincluding the Lurcher site (alanine to threonine mutation) (11,33), the R-Q RNA editing site (43), the flop-flip domains (44), and transmembrane domains (45)-have been suggested to affect the tetramerization step of the assembly, probably by changing the velocity of the second dimerization. Here, we clearly demonstrated that the GluA1 SP plays a critical role in determining the spatial arrangement of heteromeric receptor tetramerization.…”

Section: Discussionmentioning

confidence: 99%

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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Section: Discussionmentioning

confidence: 99%

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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“…2d). Although a substantial fraction of GluR2 harbors high-mannose glycans (26,27), GluR2 did not bind Fbx2 (Fig. 2 c and e).…”

Section: Identification Of Fbx2 As a Nr1-ntd-binding Partnermentioning

confidence: 93%

Activity-dependent NMDA receptor degradation mediated by retrotranslocation and ubiquitination

Kato

Rouach

Nicoll

et al. 2005

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

139

100

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The extracellular N-terminal domain (NTD) is the largest region of NMDA receptors; however, biological roles for this ectodomain remain unknown. Here, we determined that the F-box protein, Fbx2, bound to high-mannose glycans of the NR1 ectodomain. F-box proteins specify ubiquitination by linking protein substrates to the terminal E3 ligase. Indeed, ubiquitination of NR1 was increased by Fbx2 and diminished by an Fbx2 dominant-negative mutant. When expressed in hippocampal neurons, this Fbx2 dominant-negative mutant augmented NR1 subunit levels and NMDA receptor-mediated currents in an activity-dependent fashion. These results suggest that homeostatic control of synaptic NR1 involves receptor retrotranslocation and degradation by the ubiquitin-proteasome pathway.endoplasmic reticulum degradation pathway ͉ neuronal activity ͉ NFB42 ͉ proteasome ͉ ubiquitylation

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“…AMPARs containing both GluA1 and GluA2 follow GluA1 trafficking rules and override the ER retention of GluA2. Thus, GluA1/2 heteromers rapidly traffic from the ER to the surface whereas AMPARs without GluA1 or GluA4 transit much more slowly 77,78 (Fig. 3).…”

Section: Rna Editing Ampar Assembly and Er Exitmentioning

confidence: 98%

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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AMPA Receptor Tetramerization Is Mediated by Q/R Editing

Cited by 276 publications

References 51 publications

GluA1 signal peptide determines the spatial assembly of heteromeric AMPA receptors

GluA1 signal peptide determines the spatial assembly of heteromeric AMPA receptors

Activity-dependent NMDA receptor degradation mediated by retrotranslocation and ubiquitination

Synaptic AMPA receptor composition in development, plasticity and disease

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