Subunit-Specific Rules Governing AMPA Receptor Trafficking to Synapses in Hippocampal Pyramidal Neurons

Shi, Song-Hai; Hayashi, Yasunori; Esteban, José A.; Malinow, Roberto

doi:10.1016/s0092-8674(01)00321-x

Cited by 1,012 publications

(1,129 citation statements)

References 75 publications

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“…Consistent with these findings, in the current study, chronic nicotine SA increased GluR2/3 subunit levels by 30% in VTA. This finding suggests that there might be a larger pool of recycling GluR2/3 subunits in VTA neurons since these subunits are known to recycle constitutively, which is important for the maintenance of basal synaptic activity (Passafaro et al, 2001;Shi et al, 2001). We also speculate that the AMPA/NMDA EPSC ratio may be increased if more GluR2/3 subunits reside in the plasma membrane.…”

Section: Discussionmentioning

confidence: 74%

Upregulation of Ionotropic Glutamate Receptor Subunits within Specific Mesocorticolimbic Regions during Chronic Nicotine Self-Administration

Wang

Chen

Steketee

et al. 2006

Neuropsychopharmacol

119

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Nicotine, an addictive substance, is the major psychoactive component in cigarette smoke. Both a-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid and N-methyl-D-aspartate (NMDA) receptors are essential for the acute stimulative effects of nicotine on the mesocorticolimbic dopamine system, yet little is known about the effects of chronic nicotine treatment on glutamate receptors. Therefore, we used a model of chronic nicotine self-administration (SA), which emulates important aspects of nicotine intake by humans, to determine whether glutamate receptor subunits were affected. After 18 days of saline vs nicotine SA, ionotropic glutamate receptor subunit levels were determined in brain regions within the mesocorticolimbic system by Western blotting. In prefrontal cortex (PFC), the levels of NMDA receptor subunit 2A (NR2A) and NR2B were increased by 67% (p ¼ 0.04) and 83% (p ¼ 0.027), respectively. In the ventral tegmental area (VTA), glutamate receptor subunit 2/3 (GluR2/3) increased by 34% (p ¼ 0.011). Nicotine SA did not affect the expression of these subunits in dorsal striatum and nucleus accumbens. These findings suggest that chronic nicotine SA selectively increased the levels of ionotropic glutamate receptor subunits in a brain region-specific manner.

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Section: Discussionmentioning

confidence: 74%

Upregulation of Ionotropic Glutamate Receptor Subunits within Specific Mesocorticolimbic Regions during Chronic Nicotine Self-Administration

Wang

Chen

Steketee

et al. 2006

Neuropsychopharmacol

119

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“…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: 84%

“…This is mediated by CaMKII phosphorylation of GluA1 and interaction with synaptic PDZ domaincontaining proteins that recruit and retain GluA1/GluA2 AMPARs at synapses during induction of long-term potentiation (LTP) 15,16 . Once the GluA1-mediated increase in AMPAR number is established, interactions with GluA2 take over to control constitutive and activity-dependent AMPAR endocytosis, and long-term depression (LTD) 10,17 . This model fits well with the general concept that the differential trafficking of individual subunits plays fundamentally important roles in the regulation of excitatory synapses.…”

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 addition, the composition in subunits also controls the local movements of glutamate receptors (Shi et al, 2001). Few examples of subunit-specific targeting are well documented for nAChRs.…”

Section: Intracellular Targeting and Receptor Clusteringmentioning

confidence: 99%

The diversity of subunit composition in nAChRs: Evolutionary origins, physiologic and pharmacologic consequences

2002

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Nicotinic acetylcholine receptors are made up of homologous subunits, which are encoded by a large multigene family. The wide number of receptor oligomers generated display variable pharmacological properties. One of the main questions underlying research in molecular pharmacology resides in the actual role of this diversity. It is generally assumed that the observed differences between the pharmacology of homologous receptors, for instance, the EC 50 for the endogenous agonist, or the kinetics of desensitization, bear some kind of physiologic relevance in vivo. Here we develop the quite challenging point of view that, at least within a given subfamily of nicotinic receptor subunits, the pharmacologic variability observed in vitro would not be directly relevant to the function of receptor proteins in vivo. In vivo responses are not expected to be sensitive to mild differences in affinities, and several examples of functional replacement of one subunit by another have been unravelled by knockout animals. The diversity of subunits might have been conserved through evolution primarily to account for the topologic diversity of subunit distribution patterns, at the cellular and subcellular levels. A quantitative variation of pharmacological properties would be tolerated within a physiologic envelope, as a consequence of a near-neutral genetic drift. Such a "gratuitous" pharmacologic diversity is nevertheless of practical interest for the design of drugs, which would specifically tackle particular receptor oligomers with a defined subunit composition among the multiple nicotinic receptors present in the organism.

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Subunit-Specific Rules Governing AMPA Receptor Trafficking to Synapses in Hippocampal Pyramidal Neurons

Cited by 1,012 publications

References 75 publications

Upregulation of Ionotropic Glutamate Receptor Subunits within Specific Mesocorticolimbic Regions during Chronic Nicotine Self-Administration

Upregulation of Ionotropic Glutamate Receptor Subunits within Specific Mesocorticolimbic Regions during Chronic Nicotine Self-Administration

Synaptic AMPA receptor composition in development, plasticity and disease

The diversity of subunit composition in nAChRs: Evolutionary origins, physiologic and pharmacologic consequences

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