A role for sorting nexin 27 in AMPA receptor trafficking

Loo, Li Shen; Tang, Ning; Al-Haddawi, Muthafar; Dawe, Gavin S.; Hong, Wanjin

doi:10.1038/ncomms4176

Cited by 93 publications

(111 citation statements)

References 33 publications

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“…Although lacking a BAR domain, SNX27 is the only known family member to contain a PDZ domain (11,37). To date, SNX27 modulates the early endosomal trafficking of Kir3 channels (22), 5-HT4a (15), and NR2C receptors (14), and consistent with our results was recently shown to increase delivery rate of AMPA receptors as well as β-adrenergic from endosomes to plasma membrane (16,21,38,39). In each case, SNX27 acts as a PDZ-directed adaptor, binding the relevant PDZ motif on the receptor and guiding it through the endosomal pathway.…”

Section: Discussionsupporting

confidence: 75%

Sorting Nexin 27 regulates basal and activity-dependent trafficking of AMPARs

Hussain

Diering

Sole

et al. 2014

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

100

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Activity-dependent changes in synaptic strength have long been postulated as cellular correlates of learning and memory. Long-term potentiation (LTP), a well characterized form of synaptic plasticity, is often expressed as an increase in the number of postsynaptic AMPAtype glutamate receptors (AMPARs). Although the precise molecular mechanisms governing LTP remain elusive, this study identifies one member of the sorting nexin family, Sorting Nexin 27 (SNX27), as a critical component in this process. The ability of sorting nexins to bind specific phospholipids as well as their propensity to form protein-protein complexes, points to a role for these proteins in membrane trafficking and protein sorting. Here, we demonstrate that SNX27 binds to AMPARs, and that this interaction is regulated in an activity-dependent manner. Furthermore, we provide evidence that SNX27 is synaptically enriched and its level of expression regulates targeting of AMPARs to the neuronal surface. Loss of SNX27 abolishes recruitment of surface AMPARs during chemical LTP. Collectively, our data suggest a role for SNX27 in modulating synaptic plasticity through regulated interaction with AMPARs.PX domain | postsynaptic density | proteomics | PDZ-domain

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Section: Discussionsupporting

confidence: 75%

Sorting Nexin 27 regulates basal and activity-dependent trafficking of AMPARs

Hussain

Diering

Sole

et al. 2014

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

100

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“…Modulating the number and activity of synaptic AMPA-Rs contributes to the activity-dependent plasticity of the synapse that is argued to contribute to learning and memory (reviewed in [1]). SNX27 binds to the PDZ-bindingmotifs present in the GluA1 and GluA2 AMPA-R subunits and is enriched in synapses, where its presence is necessary for efficient cell surface expression of these receptors [35][36][37][38]. Chemically induced endosometo-cell surface synaptic insertion of AMPA-R, a mimic of long-term potentiation (LTP), is severely perturbed in SNX27−/− neurons and in rat cortical neurons suppressed for SNX27 expression by short-hairpin RNA [36,37].…”

Section: Discussionmentioning

confidence: 99%

“…With such a central role in controlling the cell surface levels of functionally diverse transmembrane proteins, it is not surprising that SNX27 homozygous knockoutmice are born with a non-Mendelian frequency, suggestive of in utero defects in embryonic development, and for those mice that are born, they are weaker and smaller than their littermates, display abnormal behavior and die within 4 weeks of birth [35]. Their brain pathology includes bilateral dilatation of the lateral ventricles, thinning of the cortex and dissociation of the periventricular neuropil, which is abnormally vacuolated [37].…”

Section: Discussionmentioning

confidence: 99%

“…Cargo proteins for SNX27-mediated sorting include the Menkes disease-associated copper transport ATP7A, the glucose transporter GLUT1, various metal and amino acid transporters, ion channels and numerous signaling receptors [31,32,29,25,33,28,34] that include the β2-adrenergic receptor [30,10], and the ionotropic glutamate receptors α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor (AMPA-R) and Nmethyl-D-aspartate (NMDA) receptor (NMDA-R) [35][36][37][38]. With such a central role in controlling the cell surface levels of functionally diverse transmembrane proteins, it is not surprising that SNX27 homozygous knockoutmice are born with a non-Mendelian frequency, suggestive of in utero defects in embryonic development, and for those mice that are born, they are weaker and smaller than their littermates, display abnormal behavior and die within 4 weeks of birth [35].…”

Section: Discussionmentioning

confidence: 99%

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A defect in the retromer accessory protein, SNX27, manifests by infantile myoclonic epilepsy and neurodegeneration

et al. 2015

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The composition of the neuronal cell surface dictates synaptic plasticity and thereby cognitive development. This remodeling of the synapses is governed by the endocytic network which internalize transmembrane proteins, then sort them back to the cell surface or carry them to the lysosome for degradation. The multi-protein retromer complex is central to this selection, capturing specific transmembrane proteins and remodeling the cell membrane to form isolated cargo-enriched transport carriers. We investigated a consanguineous family with four patients who presented in infancy with intractable myoclonic epilepsy and lack of psychomotor development. Using exome analysis, we identified a homozygous deleterious mutation in SNX27, which encodes sorting nexin 27, a retromer cargo adaptor. In western analysis of patient fibroblasts, the encoded mutant protein was expressed at an undetectable level when compared with a control sample. The patients' presentation and clinical course recapitulate that reported for the SNX27 knock-out mouse. Since the cargo proteins for SNX27-mediated sorting include subunits of ionotropic glutamate receptors and endosome-to-cell surface synaptic insertion of AMPA receptors is severely perturbed in SNX27−/− neurons, it is proposed that at least part of the neurological aberrations observed in the patients is attributed to defective sorting of ionotropic glutamate receptors. SNX27 deficiency is now added to the growing list of neurodegenerative disorders associated with retromer dysfunction. * Peter J. Cullen: Pete.Cullen@bristol.ac.uk. * Orly Elpeleg: Elpeleg@Hadassah.org.il. Ethical standards statement.The experiments comply with the current laws of Israel.

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“…For example, the GluA1 PDZ ligand binds selectively to Synapse-associated protein 97 (SAP97), which delivers GluA1-containing AMPARs to synapses following CaMKII activation via binding to the motor protein myosin VI 100,101 . Furthermore, the endosomal PDZ domain-containing protein SNX27 binds both GluA1 and GluA2 and is involved in both maintaining basal AMPAR surface expression in addition to mediating AMPAR insertion during LTP 102,103 . Plasticity at the cerebellar granule cell-stellate cell synapse is characterized by the replacement of synaptic CP-AMPARs with CI-AMPARs (Fig.…”

Section: Mechanisms Of 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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A role for sorting nexin 27 in AMPA receptor trafficking

Cited by 93 publications

References 33 publications

Sorting Nexin 27 regulates basal and activity-dependent trafficking of AMPARs

Sorting Nexin 27 regulates basal and activity-dependent trafficking of AMPARs

A defect in the retromer accessory protein, SNX27, manifests by infantile myoclonic epilepsy and neurodegeneration

Synaptic AMPA receptor composition in development, plasticity and disease

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