Heteromeric AMPA Receptors Assemble with a Preferred Subunit Stoichiometry and Spatial Arrangement

Mansour, Michael; Nagarajan, Naveen; Nehring, Ralf B.; Clements, John D.; Rosenmund, Christian

doi:10.1016/s0896-6273(01)00520-7

Cited by 195 publications

(206 citation statements)

References 38 publications

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“…For both wild-type and T686A channels, most openings were to the two smallest open levels, although all our results were obtained at agonist concentrations at which the channels should often be fully occupied. Similar results were obtained before for GluR4 channels (Tomita et al, 2005), and results for GluR2-Q channels and native channels in hippocampal neurons are also consistent with a predominance of openings to small conductance states at high glutamate concentrations (Mansour et al, 2001;Gebhardt and Cull-Candy, 2006).…”

Section: Analysis Of Single-channel Currentssupporting

confidence: 89%

Structural and Single-Channel Results Indicate That the Rates of Ligand Binding Domain Closing and Opening Directly Impact AMPA Receptor Gating

Zhang¹,

Cho²,

Lolis³

et al. 2008

J. Neurosci.

118

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At most excitatory central synapses, glutamate is released from presynaptic terminals and binds to postsynaptic AMPA receptors, initiating a series of conformational changes that result in ion channel opening. Efficient transmission at these synapses requires that glutamate binding to AMPA receptors results in rapid and near-synchronous opening of postsynaptic receptor channels. In addition, if the information encoded in the frequency of action potential discharge is to be transmitted faithfully, glutamate must dissociate from the receptor quickly, enabling the synapse to discriminate presynaptic action potentials that are spaced closely in time.The current view is that the efficacy of agonists is directly related to the extent to which ligand binding results in closure of the binding domain. For glutamate to dissociate from the receptor, however, the binding domain must open. Previously, we showed that mutations in glutamate receptor subunit 2 that should destabilize the closed conformation not only sped deactivation but also altered the relative efficacy of glutamate and quisqualate. Here we present x-ray crystallographic and single-channel data that support the conclusions that binding domain closing necessarily precedes channel opening and that the kinetics of conformational changes at the level of the binding domain importantly influence ion channel gating. Our findings suggest that the stability of the closed-cleft conformation has been tuned during evolution so that glutamate dissociates from the receptor as rapidly as possible but remains an efficacious agonist.

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Section: Analysis Of Single-channel Currentssupporting

confidence: 89%

Structural and Single-Channel Results Indicate That the Rates of Ligand Binding Domain Closing and Opening Directly Impact AMPA Receptor Gating

Zhang¹,

Cho²,

Lolis³

et al. 2008

J. Neurosci.

118

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“…Assembly-Several studies have suggested a role for the X domain in the assembly of multimeric channels (10,12,32,33). Furthermore, experiments performed with separately expressed extracellular domains of GluR-D subunit indicate that the X domain is able to form dimers, consistent with a role in the assembly (11).…”

Section: Discussionmentioning

confidence: 87%

“…It should be noted, however, that most native AMPA receptors are heteromeric assemblies, and while the assembly of homomeric GluR-D channels seems to occur apparently normally in the absence of the X domain, the assembly of heteromeric subunit combinations may well require participation of the N-terminal region. Interestingly, a recent elegant study provided evidence that the assembly of homomeric AMPA receptors is a stochastic process, whereas heteromeric channels assemble with a preferred subunit stoichiometry (33). Considering the highly conserved ligand-binding domain and transmembrane segments of AMPA receptor subunits, it will be of considerable interest to test whether the more variable N-terminal domain (see below) would be able to guide the preferential formation of subunit pairs in the heteromeric assembly process.…”

Section: Discussionmentioning

confidence: 99%

α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptor Channels Lacking the N-terminal Domain

Pasternack¹,

Coleman²,

Jouppila³

et al. 2002

Journal of Biological Chemistry

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Ionotropic glutamate receptor (iGluR) subunits contain a ϳ400-residue extracellular N-terminal domain ("X domain"), which is sequence-related to bacterial amino acid-binding proteins and to class C G-protein-coupled receptors. The X domain has been implicated in the assembly, transport to the cell surface, allosteric ligand binding, and desensitization in various members of the iGluR family, but its actual role in these events is poorly characterized. We have studied the properties of homomeric ␣-amino-3-hydroxy-5-methylisoxazolepropionate (AMPA)-selective GluR-D glutamate receptors carrying N-terminal deletions. Our analysis indicates that, surprisingly, transport to the cell surface, ligand binding properties, agonist-triggered channel activation, rapid desensitization, and allosteric potentiation by cyclothiazide can occur normally in the complete absence of the X domain (residues 22-402). The relatively intact ligand-gated channel function of a homomeric AMPA receptor in the absence of the X domain indirectly suggests more subtle roles for this domain in AMPA receptors, e.g. in the assembly of heteromeric receptors and in synaptic protein interactions.

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“…Both AMPA 254 and NMDA receptors 255 are probably largely formed from tetrameric, heteromeric assemblies of different subunits 256 . Changes in these receptors are probably mediated through nuclear transcription factors 257 .…”

Section: The Iglur Family Is Classified Into Three Major Subtypes a Cmentioning

confidence: 99%

A Review of Glutamate Receptors I: Current Understanding of Their Biology

Rousseaux

2008

J Toxicol Pathol

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Seventy years ago it was discovered that glutamate is abundant in the brain and that it plays a central role in brain metabolism. However, it took the scientific community a long time to realize that glutamate also acts as a neurotransmitter. Glutamate is an amino acid and brain tissue contains as much as 5 -15 mM glutamate per kg depending on the region, which is more than of any other amino acid. The main motivation for the ongoing research on glutamate is due to the role of glutamate in the signal transduction in the nervous systems of apparently all complex living organisms, including man. Glutamate is considered to be the major mediator of excitatory signals in the mammalian central nervous system and is involved in most aspects of normal brain function including cognition, memory and learning. In this review, the basic biology of the excitatory amino acids glutamate, glutamate receptors, GABA, and glycine will first be explored. In the second part of this review, the known pathophysiology and pathology will be described. (J Toxicol Pathol 2008; 21: 25-51)

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Heteromeric AMPA Receptors Assemble with a Preferred Subunit Stoichiometry and Spatial Arrangement

Cited by 195 publications

References 38 publications

Structural and Single-Channel Results Indicate That the Rates of Ligand Binding Domain Closing and Opening Directly Impact AMPA Receptor Gating

Structural and Single-Channel Results Indicate That the Rates of Ligand Binding Domain Closing and Opening Directly Impact AMPA Receptor Gating

α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptor Channels Lacking the N-terminal Domain

A Review of Glutamate Receptors I: Current Understanding of Their Biology

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