CKAMP44: A Brain-Specific Protein Attenuating Short-Term Synaptic Plasticity in the Dentate Gyrus

Engelhardt, Jakob von; Mack, Volker; Sprengel, Rolf; Kavenstock, Netta; Li, Ka Wan; Stern‐Bach, Yael; Smit, August B.; Seeburg, Peter H.; Monyer, Hannah

doi:10.1126/science.1184178

Cited by 233 publications

(345 citation statements)

References 21 publications

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“…This seemingly straightforward conclusion may be complicated by several issues. First, AMPA-Rs interact with other proteins, including cytosine-knot AMPA-R-modulating protein 44 (CKAMP44) and cornichons (41,42); and both AMPA-Rs and their auxiliary subunits, including TARPs, are subject to posttranslational modification-factors that could affect the relative efficacy of kainate vs. glutamate in neurons. Second, it was unclear whether the actions of TARPs are equivalent for tethered and nontethered conditions at each of the stoichiometries.…”

Section: Discussionmentioning

confidence: 99%

“…With the future development of more photostable red and blue fluorescent proteins that can be used for single-molecule experiments, it should become possible to determine the subunit composition for two interacting partners at the same time. This will open the way for elucidating complexes formed by mixtures of GluA1 and GluA2 receptor subunits with TARPs, and the interaction between TARPs and other newly discovered AMPA-R-interacting proteins such as cornichons (41) and CKAMP44 (42).…”

Section: Discussionmentioning

confidence: 99%

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AMPA receptor/TARP stoichiometry visualized by single-molecule subunit counting

Hastie

Ulbrich

Wang

et al. 2013

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

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Members of the transmembrane AMPA receptor-regulatory protein (TARP) family modulate AMPA receptor (AMPA-R) trafficking and function. AMPA-Rs consist of four pore-forming subunits. Previous studies show that TARPs are an integral part of the AMPA-R complex, acting as accessory subunits for mature receptors in vivo. The TARP/AMPA-R stoichiometry was previously measured indirectly and found to be variable and dependent on TARP expression level, with at most four TARPs associated with each AMPA-R complex. Here, we use a single-molecule technique in live cells that selectively images proteins located in the plasma membrane to directly count the number of TARPs associated with each AMPA-R complex. Although individual GFP-tagged TARP subunits are observed as freely diffusing fluorescent spots on the surface of Xenopus laevis oocytes when expressed alone, coexpression with AMPA-RmCherry immobilizes the stargazin-GFP spots at sites of AMPA-RmCherry, consistent with complex formation. We determined the number of TARP molecules associated with each AMPA-R by counting bleaching steps for three different TARP family members: γ-2, γ-3, and γ-4. We confirm that the TARP/AMPA-R stoichiometry depends on TARP expression level and discover that the maximum number of TARPs per AMPA-R complex falls into two categories: up to four γ-2 or γ-3 subunits, but rarely above two for γ-4 subunit. This unexpected AMPA-R/TARP stoichiometry difference has important implications for the assembly and function of TARP/ AMPA-R complexes.single-molecule counting | TIRF | glutamate receptors | stargazin G lutamate is the main excitatory neurotransmitter in the mammalian CNS. Most fast excitatory synaptic transmission in the brain is mediated by AMPA receptors (AMPA-Rs). Four AMPA-R subunits, GluA1-4, contribute to the heterotetrameric assemblies of the AMPA-R (1-4). The localization of AMPA-Rs to the postsynaptic membrane is regulated by a large number of proteins through multiple mechanisms and plays important roles in synaptic plasticity (5-9).Transmembrane AMPA-R regulatory proteins (TARPs) represent a family of AMPA-R regulatory proteins that are tightly associated with AMPA-Rs, and can be considered auxiliary AMPA-R subunits (10-12). TARPs regulate AMPA-R function by several mechanisms. They mediate the efficient cell surface expression of AMPA-Rs, modulate gating, affect agonist efficacy, and even attenuate intracellular polyamine block of calciumpermeable AMPA-Rs (13-22). The effect of stargazin (γ-2) and other TARPs on GluA1 is not neuron specific and can be accurately mimicked in nonneuronal mammalian cells (18,(23)(24)(25), as well as Xenopus oocytes (13,14,17,26,27), suggesting that the basic mechanisms for TARP/AMPA-R interaction and TARPmediated regulation of AMPA-R trafficking are preserved in nonneuronal cells.Although much is known about the interaction domains on the classical TARPs (γ-2, γ-3, γ-4, and γ-8) and AMPA-Rs that mediate assembly and modulation (13,23,24,27,28), far less is known about the stoichiometry of the TARP/AMPA-R...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

AMPA receptor/TARP stoichiometry visualized by single-molecule subunit counting

Hastie

Ulbrich

Wang

et al. 2013

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

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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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“…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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CKAMP44: A Brain-Specific Protein Attenuating Short-Term Synaptic Plasticity in the Dentate Gyrus

Cited by 233 publications

References 21 publications

AMPA receptor/TARP stoichiometry visualized by single-molecule subunit counting

AMPA receptor/TARP stoichiometry visualized by single-molecule subunit counting

Synaptic AMPA receptor composition in development, plasticity and disease

GluA1 signal peptide determines the spatial assembly of heteromeric AMPA receptors

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