SynDIG1: An Activity-Regulated, AMPA- Receptor-Interacting Transmembrane Protein that Regulates Excitatory Synapse Development

Kalashnikova, Evgenia; Lorca, Ramón A.; Kaur, Inderpreet; Barisone, Gustavo A.; Li, Bonnie; Ishimaru, Tatsuto; Trimmer, James S.; Mohapatra, Durga P.; Díaz, Elizabeth

doi:10.1016/j.neuron.2009.12.021

Cited by 132 publications

(154 citation statements)

References 39 publications

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“…Currently identified AMPAR auxiliary subunits include TARPs, suppressor of lurcher (SOL) 110 , Cornichon homologues (CNIHs) 111 , synapse differentiation-induced genes (SynDIG I and SynDIG4) 112,113 , cysteine-knot AMPAR modulating protein family 114,115 , and germ cell-specific gene 1-like (GSG1L) protein 116 . Of these the prototypical TARP family of AMPAR auxiliary subunits are by far the best characterized.…”

Section: Ampar Auxiliary Subunitsmentioning

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: Ampar Auxiliary Subunitsmentioning

confidence: 99%

Synaptic AMPA receptor composition in development, plasticity and disease

2016

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“…These data further supported the notion that, in the heteromeric GluA1/A2 receptor, the dimer of dimers interface in LBDs is between GluA1 subunits. AMPARs are modulated by auxiliary subunits in the brain, including TARPs, cornichons, GSG1L, SynDIG1, CKAMP44, and other proteins (23)(24)(25)(26)(27)(28). Among them, TARPs are reported to affect AMPAR synthesis, maturation, trafficking, and function (29).…”

Section: Glua1 and Glua2 Have Preferred Positions In Tetrameric Assemmentioning

confidence: 99%

GluA1 signal peptide determines the spatial assembly of heteromeric AMPA receptors

Kalyanaraman

et al. 2016

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

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AMPA-type glutamate receptors (AMPARs) mediate fast excitatory neurotransmission and predominantly assemble as heterotetramers in the brain. Recently, the crystal structures of homotetrameric GluA2 demonstrated that AMPARs are assembled with two pairs of conformationally distinct subunits, in a dimer of dimers formation. However, the structure of heteromeric AMPARs remains unclear. Guided by the GluA2 structure, we performed cysteine mutant cross-linking experiments in fulllength GluA1/A2, aiming to draw the heteromeric AMPAR architecture. We found that the amino-terminal domains determine the first level of heterodimer formation. When the dimers further assemble into tetramers, GluA1 and GluA2 subunits have preferred positions, possessing a 1-2-1-2 spatial assembly. By swapping the critical sequences, we surprisingly found that the spatial assembly pattern is controlled by the excisable signal peptides. Replacements with an unrelated GluK2 signal peptide demonstrated that GluA1 signal peptide plays a critical role in determining the spatial priority. Our study thus uncovers the spatial assembly of an important type of glutamate receptors in the brain and reveals a novel function of signal peptides.AMPA receptors | signal peptide | spatial assembly | stoichiometry

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“…They can modulate the functional characteristics of iGluRs and may also mediate surface trafficking and/or targeting to specific subcellular compartments (Jackson and Nicoll 2011). Auxiliary proteins described so far include stargazin and its relatives (Tomita et al 2003;Milstein and Nicoll 2008), cornichon homolog-2 and homolog-3 (Schwenk et al 2009), Cysteine-knot AMPAR-modulating protein (von Engelhardt et al 2010), SynDIG1 (Kalashnikova et al 2010), neuropillin and tolloid-like proteins Neto1 and Neto2 (Ng et al 2009;Zhang et al 2009), and Caenorhabditis elegans SOL-1 (Zheng et al 2004). Studies in tissue culture and heterologous systems suggested that some of the auxiliary subunits have the potential to contribute to clustering of iGluRs, since they promote the accumulation of receptors at the cell surface (for review, see Jackson and Nicoll 2011).…”

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confidence: 99%

Drosophila Neto is essential for clustering glutamate receptors at the neuromuscular junction

Kim

Bao²,

Bonanno³

et al. 2012

Genes Dev.

111

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Neurotransmitter receptor recruitment at postsynaptic specializations is key in synaptogenesis, since this step confers functionality to the nascent synapse. The Drosophila neuromuscular junction (NMJ) is a glutamatergic synapse, similar in composition and function to mammalian central synapses. Various mechanisms regulating the extent of postsynaptic ionotropic glutamate receptor (iGluR) clustering have been described, but none are known to be essential for the initial localization and clustering of iGluRs at postsynaptic densities (PSDs). We identified and characterized the Drosophila neto (neuropilin and tolloid-like) as an essential gene required for clustering of iGluRs at the NMJ. Neto colocalizes with the iGluRs at the PSDs in puncta juxtaposing the active zones. neto loss-of-function phenotypes parallel the loss-of-function defects described for iGluRs. The defects in neto mutants are effectively rescued by muscle-specific expression of neto transgenes. Neto clustering at the Drosophila NMJ coincides with and is dependent on iGluRs. Our studies reveal that Drosophila Neto is a novel, essential component of the iGluR complexes and is required for iGluR clustering, organization of PSDs, and synapse functionality.

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SynDIG1: An Activity-Regulated, AMPA- Receptor-Interacting Transmembrane Protein that Regulates Excitatory Synapse Development

Cited by 132 publications

References 39 publications

Synaptic AMPA receptor composition in development, plasticity and disease

Synaptic AMPA receptor composition in development, plasticity and disease

GluA1 signal peptide determines the spatial assembly of heteromeric AMPA receptors

Drosophila Neto is essential for clustering glutamate receptors at the neuromuscular junction

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