AMPA Receptor Assembly: Atomic Determinants and Built-In Modulators

Sukumaran, Madhav; Penn, Andrew C.; Greger, Ingo H.

doi:10.1007/978-3-7091-0932-8_11

Cited by 26 publications

(31 citation statements)

References 116 publications

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“…8) that accommodates our experimental results with the body of current research literature on AMPA receptor assembly (for reviews, see Refs. [35][36][37][38]. The crystal structure of GluA2 tetramers shows that the LBDs and NTDs are organized as pairs of dimers, one subunit in each pair occupying a proximal and the other a distal position around the central axis, whereas the membrane-associated regions are arranged around the ion channel in a 4-fold symmetrical fashion (10).…”

Section: Discussionmentioning

confidence: 99%

Aggregation Limits Surface Expression of Homomeric GluA3 Receptors

Coleman¹,

Hou²,

Willibald³

et al. 2016

Journal of Biological Chemistry

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AMPA receptors are glutamate-gated cation channels assembled from GluA1-4 subunits and have properties that are strongly dependent on the subunit composition. The subunits have different propensities to form homomeric or various heteromeric receptors expressed on cell surface, but the underlying mechanisms are still poorly understood. Here, we examined the biochemical basis for the poor ability of GluA3 subunits to form homomeric receptors, linked previously to two amino acid residues, Tyr-454 and Arg-461, in its ligand binding domain (LBD). Surface expression of GluA3 was improved by co-assembly with GluA2 but not with stargazin, a trafficking chaperone and modulator of AMPA receptors. The secretion efficiency of GluA2 and GluA3 LBDs paralleled the transport difference between the respective full-length receptors and was similarly dependent on Tyr-454/Arg-461 but not on LBD stability. In comparison to GluA2, GluA3 homomeric receptors showed a strong and Tyr-454/Arg-461-dependent tendency to aggregate both in the macroscopic scale measured as lower solubility in nonionic detergent and in the microscopic scale evident as the preponderance of hydrodynamically large structures in density gradient centrifugation and native gel electrophoresis. We conclude that the impaired surface expression of homomeric GluA3 receptors is caused by nonproductive assembly and aggregation to which LBD residues Tyr-454 and Arg-461 strongly contribute. This aggregation inhibits the entry of newly synthesized GluA3 receptors to the secretory pathway.␣-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors are tetrameric ligand-gated ion channels that mediate fast excitatory neurotransmission in vertebrate brain (1, 2). The functional properties of AMPA receptors, including channel kinetics, ion permeability, ligand pharmacology, and regulation, are determined by the subunit composition. AMPA receptors are built from four subunit types (GluA1-4), each expressed as multiple alternatively spliced and/or RNA-edited variants. Studies with native and recombinant receptors indicate that receptor assembly is not random but strongly favors certain subunit combinations (3, 4). The majority of native AMPA receptors are heteromers of edited GluA2 subunits with GluA1 or GluA3 subunits, forming channels that are impermeable to Ca 2ϩ and showing a linear current-voltage (I-V) relation (3, 5, 6). Minor native populations of homomeric AMPA receptors are formed by GluA1 or GluA4 subunits to produce inwardly rectifying and Ca 2ϩ -permeable channels (7,8).At present, the molecular logic underlying the formation and cellular processing of specific subunit assemblies in AMPA receptors is still poorly understood. The oligomerization is initiated by formation of dimers between N-terminal domains (NTD) 5 of nascent receptor polypeptides in the endoplasmic reticulum (ER) followed by interactions involving the transmembrane segments and the ligand binding domains (LBD) (9 -11). The relative strength of NTD contacts can partly explain the strong prefe...

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Section: Discussionmentioning

confidence: 99%

Aggregation Limits Surface Expression of Homomeric GluA3 Receptors

Coleman¹,

Hou²,

Willibald³

et al. 2016

Journal of Biological Chemistry

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“…16,18,59; for reviews, see Refs. [63][64][65], and point mutations in the NTD can lead to impaired maturation and surface expression (18,59). Nascent receptor dimers held together by N-terminal dimerization and by transmembrane segment packing, but with clearly separate LBDs, have been identified in an electron microscopic analysis of AMPA receptor biosynthesis (16).…”

Section: Discussionmentioning

confidence: 99%

“…Nascent receptor dimers held together by N-terminal dimerization and by transmembrane segment packing, but with clearly separate LBDs, have been identified in an electron microscopic analysis of AMPA receptor biosynthesis (16). The subsequent dimer-to-tetramer transition is thought to be driven by interdimer contacts forming between the transmembrane and NTD regions and to involve the dimerization of LBDs across the original dimers (9,16,64,65). From this scheme, it can be predicted that, in the absence of the NTD, the rates of initial dimerization and the subsequent dimer-to-tetramer transition would be affected severely.…”

Section: Discussionmentioning

confidence: 99%

The N-terminal Domain Modulates α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) Receptor Desensitization

Möykkynen

Coleman

Semenov

et al. 2014

Journal of Biological Chemistry

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“…6 AMPAR tetramers are formed in the endoplasmic reticulum (ER) as a dimer of dimers 72,73 . The initial dimerization of two subunits is dependent on interactions between their N-terminal domains (NTD) followed by a second dimerization step mediated by associations at the ligand binding and membrane domains 74 .…”

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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AMPA Receptor Assembly: Atomic Determinants and Built-In Modulators

Cited by 26 publications

References 116 publications

Aggregation Limits Surface Expression of Homomeric GluA3 Receptors

Aggregation Limits Surface Expression of Homomeric GluA3 Receptors

The N-terminal Domain Modulates α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) Receptor Desensitization

Synaptic AMPA receptor composition in development, plasticity and disease

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