Subunit Composition of Synaptic AMPA Receptors Revealed by a Single-Cell Genetic Approach

Lü, Wei; Shi, Yun; Jackson, Alexander C.; Bjorgan, Kirsten M.; During, Matthew J.; Sprengel, Rolf; Seeburg, Peter H.; Nicoll, Roger A.

doi:10.1016/j.neuron.2009.02.027

Cited by 565 publications

(638 citation statements)

References 82 publications

(138 reference statements)

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“…The ionotropic glutamate receptor family comprises the AMPA, kainate and NMDA receptors, which mediate most excitatory neurotransmission in the central nervous system and function by opening a transmembrane ion channel on binding of glutamate (Lu et al, 2009). The AMPA receptor subfamily forms functional heterotetramers composed of four types of subunits, designated GluR1 (GRIA1), GluR2 (GRIA2), GluR3 (GRIA3) and GluR4 (GRIA4), whereas the AMPA receptor activity is largely dependent on the AMPA receptor composition and in particular on the presence and processing of the GluR2 subunit.…”

Section: Introductionmentioning

confidence: 99%

Dissection of mitogenic and neurodegenerative actions of cystine and glutamate in malignant gliomas

et al. 2010

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Malignant glioma represents one of the most aggressive and lethal human neoplasias. A hallmark of gliomas is their rapid proliferation and destruction of vital brain tissue, a process in which excessive glutamate release by glioma cells takes center stage. Pharmacologic antagonism with glutamate signaling through ionotropic glutamate receptors attenuates glioma progression in vivo, indicating that glutamate release by glioma cells is a prerequisite for rapid glioma growth. Glutamate has been suggested to promote glioma cell proliferation in an autocrine or paracrine manner, in particular by activation of the (RS)-a-amino-3-hydroxy-5-methylisoxazole-4-propionic acid hydrate (AMPA) subtype of glutamate receptors. Here, we dissect the effects of glutamate secretion on glioma progression. Glioma cells release glutamate through the amino-acid antiporter system X c À , a process that is mechanistically linked with cystine incorporation. We show that disrupting glutamate secretion by interfering with the system X c À activity attenuates glioma cell proliferation solely cystine dependently, whereas glutamate itself does not augment glioma cell growth in vitro. Neither AMPA receptor agonism nor antagonism affects glioma growth in vitro. On a molecular level, AMPA insensitivity is concordant with a pronounced transcriptional downregulation of AMPA receptor subunits or overexpression of the fully edited GluR2 subunit, both of which block receptor activity. Strikingly, AMPA receptor inhibition in tumorimplanted brain slices resulted in markedly reduced tumor progression associated with alleviated neuronal cell death, suggesting that the ability of glutamate to promote glioma progression strictly requires the tumor microenvironment. Concerning a potential pharmacotherapy, targeting system X c À activity disrupts two major pathophysiological properties of glioma cells, that is, the induction of excitotoxic neuronal cell death and incorporation of cystine required for rapid proliferation.

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Section: Introductionmentioning

confidence: 99%

Dissection of mitogenic and neurodegenerative actions of cystine and glutamate in malignant gliomas

et al. 2010

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“…Immuno-gold staining and electron microscopy studies have estimated that GluA3 is present at only ~10% of GluA1 or GluA2 levels 7 . Moreover, single cell deletion studies reported that ~80% of synaptic AMPARs in CA1 hippocampal neurons comprise GluA1/GluA2 hetromers 8 . However, other studies of subunit abundance in rat hippocampus and cortex suggest AMPARs comprise mainly heteromers containing GluA1 and GluA2 or GluA2 and GluA3 [8][9][10] with approximately equivalent amounts of each heteromer complex 11 .…”

Section: Subunit-specific Traffickingmentioning

confidence: 99%

“…Moreover, single cell deletion studies reported that ~80% of synaptic AMPARs in CA1 hippocampal neurons comprise GluA1/GluA2 hetromers 8 . However, other studies of subunit abundance in rat hippocampus and cortex suggest AMPARs comprise mainly heteromers containing GluA1 and GluA2 or GluA2 and GluA3 [8][9][10] with approximately equivalent amounts of each heteromer complex 11 . GluA4, on the other hand is tightly developmentally regulated and is sparsely expressed at glutamatergic synapses in principal neurons in adult brain 12 .…”

Section: Subunit-specific Traffickingmentioning

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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“…In the adult hippocampus, the AMPAR consists mainly of GluA1/GluA2 and, to a lesser extent, GluA2/GluA3 hetero-tetramers 34 . GluA1 mediates activity-dependent synaptic targeting and removal of the AMPAR during LTP 17, 19 and LTD 14 , in part through phosphorylation and dephosphorylation of its cytoplasmic domain 35 .…”

Section: Pleiotropic Effects Of Stim2 On Glua1 Traffickingmentioning

confidence: 99%

STIM2 regulates AMPA receptor trafficking and plasticity at hippocampal synapses

Yap

Shetty

García-Alvarez

et al. 2017

Neurobiology of Learning and Memory

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STIM2 is an integral membrane protein of the endoplasmic reticulum (ER) that regulates the activity of plasma membrane (PM) channels at ER-PM contact sites. Recent studies show that STIM2 promotes spine maturation and surface expression of the AMPA receptor (AMPAR) subunit GluA1, hinting to a probable role in synaptic plasticity. Here, we used a Stim2 cKO mouse line to explore the function of STIM2 in early forms of Long-Term Potentiation (E-LTP) and Depression (E-LTD), two widely-studied models of synaptic plasticity implicated in information storage. We found that STIM2 is required for the stable expression of both E-LTP and E-LTD at CA3-CA1 hippocampal synapses. Altered plasticity in Stim2 cKO mice is associated with subtle alterations in the shape and density of dendritic spines in CA1 neurons.Further, surface delivery of GluA1 in response to LTP-inducing chemical manipulations was markedly reduced in excitatory neurons derived from Stim2 cKO mice. In addition, NMDAinduced GluA1 endocytosis, which underlies LTD, was impaired in Stim2 cKO neurons. We conclude that STIM2 facilitates synaptic delivery and removal of AMPARs and regulates activity-dependent changes in synaptic strength through a unique mode of communication between the ER and the synapse.

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Subunit Composition of Synaptic AMPA Receptors Revealed by a Single-Cell Genetic Approach

Cited by 565 publications

References 82 publications

Dissection of mitogenic and neurodegenerative actions of cystine and glutamate in malignant gliomas

Dissection of mitogenic and neurodegenerative actions of cystine and glutamate in malignant gliomas

Synaptic AMPA receptor composition in development, plasticity and disease

STIM2 regulates AMPA receptor trafficking and plasticity at hippocampal synapses

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