Interaction with the Unfolded Protein Response Reveals a Role for Stargazin in Biosynthetic AMPA Receptor Transport

Vandenberghe, Wim; Nicoll, Roger A.; Bredt, David S.

doi:10.1523/jneurosci.3568-04.2005

Cited by 109 publications

(81 citation statements)

References 47 publications

(68 reference statements)

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“…More specifically, TARPs act as chaperones that prevent ER exit of incorrectly folded AMPARs 84 . Moreover, TARPs are essential for ER export of correctly assembled receptors 85 and remain part of the AMPAR complex throughout Golgi processing and forward trafficking to eventual surface expression at the postsynaptic density 86 . Similarly, cornichons have a welldefined role in the export of specific proteins from the ER 87,88 including AMPARs 89,90 .…”

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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Section: Rna Editing Ampar Assembly and Er Exitmentioning

confidence: 99%

Synaptic AMPA receptor composition in development, plasticity and disease

2016

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“…The present study found that GluR2, but not GluR3, is attenuated at synapses in vivo and in vitro in a chronic manner. GluR1/2 heteromers are assembled in the endoplasmic reticulum, and the assembled hetero-tetramers remain as a functional unit while being transported into dendrites by vesicles (Vandenberghe et al, 2005). It is now well established that regulation of synaptic GluR1/2 trafficking is a complex, multifaceted process.…”

Section: Regulation Of Ampa Receptor Trafficking By Antimanic Agents mentioning

confidence: 99%

The Role of Hippocampal GluR1 and GluR2 Receptors in Manic-Like Behavior

Du¹,

Creson²,

Ren³

et al. 2008

J. Neurosci.

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The cellular basis underlying the complex clinical symptomatology of bipolar disorder and the mechanisms underlying the actions of its effective treatments have not yet been fully elucidated. This study investigated the role of hippocampal synaptic AMPA receptors. We found that chronic administration of the antimanic agents lithium and valproate (VPA) reduced synaptic AMPA receptor GluR1/2 in hippocampal neurons in vitro and in vivo. Electrophysiological studies confirmed that the AMPA/NMDA ratio was reduced in CA1 regions of hippocampal slices from lithium-treated animals. Reduction in GluR1 phosphorylation at its cAMP-dependent protein kinase A site by the synthetic peptide TAT-S845, which mimics the effects of lithium or VPA, was sufficient to attenuate surface and synaptic GluR1/2 levels in hippocampal neurons in vitro and in vivo. Intrahippocampal infusion studies with the AMPA-specific inhibitor GYKI [4-(8-methyl-9H-1,3-dioxolo[4,5-h][2,3]benzodiazepin-5-yl)-benzenamine hydrochloride], a GluR1-specific TAT-S845 peptide, showed that GluR1/2 was essential for the development of manic/hedonic-like behaviors such as amphetamine-induced hyperactivity. These studies provide novel insights into the role of hippocampal GluR1/2 receptors in mediating facets of the manic syndrome and offer avenues for the development of novel therapeutics for these disorders.

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“…Two recent studies found the interaction of stargazin and other TARPs with AMPARs to be the most robust and least transient compared with other putative interactions, including those with 4.1 proteins (Fukata et al, 2005;Vandenberghe et al, 2005). Indeed, TARPs function as auxiliary subunits of AMPARs and are important determinants of AMPAR trafficking and synaptic anchoring.…”

Section: 1g/n Double Mutants Is Not Changedmentioning

confidence: 99%

The function of glutamatergic synapses is not perturbed by severe knockdown of 4.1N and 4.1G expression

Wozny

Breustedt

Wolk

et al. 2009

Journal of Cell Science

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AMPA-type glutamate receptors mediate fast excitatory synaptic transmission in the vertebrate brain. Their surface expression at synapses between neurons is regulated in an activity-dependent and activity-independent manner. The protein machinery that regulates synaptic targeting, anchoring and turnover of AMPA receptors consists of several types of specialized scaffolding proteins. The FERM domain scaffolding proteins 4.1G and 4.1N were previously suggested to act jointly in binding and regulating synaptic trafficking of the AMPA receptor subunits GluR1 and GluR4. To determine the functions of 4.1G and 4.1N in vivo, we generated a mutant mouse line that lacks 4.1G entirely and expresses 4.1N at 22% of wild-type levels. These mice had combined 4.1G and 4.1N protein expression in the hippocampus at 12% of wild-type levels (equivalent to 8-10% of combined GluR1 and GluR4 expression levels). They show a moderate reduction in synaptosomal expression levels of the AMPA receptor subunit GluR1 at 3 weeks of age, but no change in basic glutamatergic synaptic transmission and long-term potentiation in the hippocampus. Our study indicates that 4.1G and 4.1N do not have a crucial role in glutamatergic synaptic transmission and the induction and maintenance of long-term plastic changes in synaptic efficacy.

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Interaction with the Unfolded Protein Response Reveals a Role for Stargazin in Biosynthetic AMPA Receptor Transport

Cited by 109 publications

References 47 publications

Synaptic AMPA receptor composition in development, plasticity and disease

Synaptic AMPA receptor composition in development, plasticity and disease

The Role of Hippocampal GluR1 and GluR2 Receptors in Manic-Like Behavior

The function of glutamatergic synapses is not perturbed by severe knockdown of 4.1N and 4.1G expression

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