RNA Editing at Arg607 Controls AMPA Receptor Exit from the Endoplasmic Reticulum

Greger, Ingo H.; Khatri, Latika; Ziff, Edward B.

doi:10.1016/s0896-6273(02)00693-1

Cited by 318 publications

(337 citation statements)

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“…ER retention mechanisms are considered to exert quality control for trafficking of proteins to the plasma membrane (21). The delivery of properly folded and assembled ion channels to the plasma membrane is a crucial process for ion homeostasis in the cell, and more delivery of channels to the synaptic sites in excitable cells is of particular importance for synaptic transmission as shown by the GluR2 subunit of the ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor and the NR1 subunit of N-methyl-D-aspartate receptors (22,23). Previous studies localized ASIC1a to the dendrites, postsynaptic sites in dendritic spines, and the soma (3,13,15,24,25).…”

Section: Discussionmentioning

confidence: 99%

Activation of Acid-sensing Ion Channel 1a (ASIC1a) by Surface Trafficking

Chai

Branigan

et al. 2010

Journal of Biological Chemistry

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Acid-sensing ion channels (ASICs) are voltage-independent Na ؉ channels activated by extracellular protons. ASIC1a is expressed in neurons in mammalian brain and is implicated in long term potentiation of synaptic transmission that contributes to learning and memory. In ischemic brain injury, however, activation of this Ca 2؉ -permeable channel plays a critical role in acidosis-mediated, glutamate-independent, Ca 2؉ toxicity. We report here the identification of insulin as a regulator of ASIC1a surface expression. In modeled ischemia using Chinese hamster ovary cells, serum depletion caused a significant increase in ASIC1a surface expression that resulted in the potentiation of ASIC1a activity. Among the components of serum, insulin was identified as the key factor that maintains a low level of ASIC1a on the plasma membrane. Neurons subjected to insulin depletion increased surface expression of ASIC1a with resultant potentiation of ASIC1a currents. Intracellularly, ASIC1a is predominantly localized to the endoplasmic reticulum in Chinese hamster ovary cells, and this intracellular localization is also observed in neurons. Under conditions of serum or insulin depletion, the intracellular ASIC1a is translocated to the cell surface, increasing the surface expression level. These results reveal an important trafficking mechanism of ASIC1a that is relevant to both the normal physiology and the pathological activity of this channel.Acid-sensing ion channels belong to the epithelial sodium channel and degenerin family of ion channels and primarily transport Na ϩ into cells. ASICs 2 are activated by the presence of extracellular protons, which serve as ligands for these channels. So far six isoforms of ASICs (ASIC1a, 1b, 2a, 2b, 3, and 4) have been found in the mammalian central and peripheral nervous system. ASIC1a is expressed in various regions of brain including hippocampus, cerebral cortex, cerebellum, and amygdala (1-3). The role of ASIC1a in brain function is well characterized, in particular by electrophysiological and behavioral studies of ASIC1a knock-out (ASIC1aH ϩ -evoked currents are involved in synaptic transmission that contributes to important normal brain functions such as learning and memory in hippocampus and fear-related behaviors in the amygdala (3-5). Like other ASIC isoforms, the amino acid sequence of ASIC1a reveals a structure highly conserved among the epithelial sodium channel family (6). The crystal structure of a truncated chicken ASIC1a channel determined that this two-transmembrane protein is assembled as a trimer (7). Cerebral neurons express native ASIC1a as an assembly of homomultimers as well as heteromultimers in association with ASIC2a (8). Although ASIC1a and ASIC2a share high homology in their amino acid sequences, these proton-activated channels exhibit distinct sensitivity to extracellular pH. ASIC1a is more sensitive to changes in extracellular proton levels than ASIC2a and thus activates at a higher pH (pH of halfmaximal channel activation pH 0.5 ϭ 6.2), whereas ASIC2a activate...

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Section: Discussionmentioning

confidence: 99%

Activation of Acid-sensing Ion Channel 1a (ASIC1a) by Surface Trafficking

Chai

Branigan

et al. 2010

Journal of Biological Chemistry

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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.

140

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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“…Most assembled AMPAR tetramers contain GluA2 9 and this is strongly regulated by Q/R editing of the GluA2 subunit. GluA1 is not edited and in the absence of GluA2 assembles into CP-AMPARs that can be rapidly exported from the ER and trafficked to the plasma membrane 76 . Unedited GluA2(Q607), where it exists, also traffics rapidly through the ER to the plasma membrane.…”

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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RNA Editing at Arg607 Controls AMPA Receptor Exit from the Endoplasmic Reticulum

Cited by 318 publications

References 59 publications

Activation of Acid-sensing Ion Channel 1a (ASIC1a) by Surface Trafficking

Activation of Acid-sensing Ion Channel 1a (ASIC1a) by Surface Trafficking

Activity-dependent NMDA receptor degradation mediated by retrotranslocation and ubiquitination

Synaptic AMPA receptor composition in development, plasticity and disease

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