Measurement of Conformational Changes accompanying Desensitization in an Ionotropic Glutamate Receptor

Armstrong, N.; Jasti, Jaysankar; Beich-Frandsen, Mads; Gouaux, Eric

doi:10.1016/j.cell.2006.08.037

Cited by 204 publications

(293 citation statements)

References 38 publications

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“…Although there is no direct evidence that LBD closure necessarily precedes channel gating, these and other results strongly suggest that closing of the LBD is the initial large-scale conformational change that triggers the subsequent gating rearrangements that result in channel opening and desensitization (Sun et al, 2002;Robert et al, 2005;Valentine and Palmer, 2005;Armstrong et al, 2006;Mayer, 2006;Ahmed et al, 2007;Hansen et al, 2007). The available evidence therefore indicates that, for glutamate to be an effective and fast neurotransmitter, the kinetics of LBD closing and opening must be such that two apparently opposing requirements are met: the LBD must be closed for effective gating but open for glutamate to dissociate.…”

Section: Introductionmentioning

confidence: 92%

“…After glutamate binds to the open-cleft conformation of the LBD of an individual subunit (states 0 and 1), the cleft closes, resulting in an intermediate state (state 2) in which both the LBD and ion channel pore are closed. The inherent instability of this state is relieved by either pore rearrangements that open the channel or subunit rearrangements along the dimer interface that result in desensitization (Sun et al, 2002;Robert et al, 2005;Armstrong et al, 2006). In this model, the relative occupancies of the bound closed-channel states in which the LBD is open or closed (states 1 and 2) depend on the ratio of the rate constants CC and CO (Fig.…”

Section: T686a Alters the Relative Efficacy Of Glutamate And Quisqualatementioning

confidence: 99%

“…State 2, in which the LBD and the channel pore are closed, is unstable, and the instability is relieved by either channel opening (state 3) or rearrangement of the dimer interface and desensitization (state 4) (Sun et al, 2002). Rearrangement of the dimer interface dissipates the work done on the transmembrane helices by LBD closure and results in a long-lived closed state in which the LBD of one subunit in the dimer is stabilized in the closed-cleft conformation (Robert and Howe, 2003;Armstrong et al, 2006). h, Hypothetical plot of the occupancy of state 2 (relative to state 1) for an individual subunit.…”

Section: T686a Alters the Relative Efficacy Of Glutamate And Quisqualatementioning

confidence: 99%

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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: Introductionmentioning

confidence: 92%

Section: T686a Alters the Relative Efficacy Of Glutamate And Quisqualatementioning

confidence: 99%

Section: T686a Alters the Relative Efficacy Of Glutamate And Quisqualatementioning

confidence: 99%

See 1 more Smart Citation

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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“…The GluR2-S1S2 (for the FTIR experiments) and S1S2-T394C-S652C (for the FRET experiments) proteins were purified as described previously (9,(15)(16)(17). In brief, E. coli Origami B (DE3) cells were used to express the protein, which was then purified using a Ni-NTA HiTrap column (GE Healthcare Life Sciences, Piscataway, NJ).…”

Section: Preparation and Purification Of Glur2-s1s2 And S1s2-t394c-s6mentioning

confidence: 99%

Chemical Interplay in the Mechanism of Partial Agonist Activation in α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid Receptors

et al. 2007

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Abstractα-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, one subtype in the family of ionotropic glutamate receptors, are the main receptors responsible for excitatory signaling in the mammalian central nervous system. Previous studies utilitizing the isolated ligand binding domain of these receptors have provided insight into the role of specific ligand-protein interactions in mediating receptor activation. However, these studies relied heavily on the partial agonist kainate, in which the α-amine group is constrained in a pyrrolidine ring. Here we have studied a series of substituted and unsubstituted willardiines with primary α-amine groups similar to that of the full agonist glutamate whose activation can be varied depending on the size of the substituent. The specific ligand-protein interactions in the mechanism of partial agonism in this subtype were investigated using vibrational spectroscopy and the large scale conformational changes in the ligand binding domain were studied with fluorescence resonance energy transfer (FRET). These investigations show that the strength of the interaction at the α-amine group correlates with the extent of cleft closure and extent of activation, with the agonist of higher efficacy showing larger cleft closure and stronger interactions at this group, suggesting that this is one of the mechanisms by which the agonist controls receptor activation.α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, one subtype of ionotropic glutamate receptors, are responsible for mediating the majority of excitatory synaptic signaling in the central nervous system. Activation of these channels occurs when an agonist, such as glutamate, binds in the bilobed extracellular ligand binding domain of the receptor, initiating a series of conformational changes that lead to the formation of cation selective channels (1-4).Recent vibrational spectroscopic investigations (5-8) in combination with fluorescence resonance energy transfer (FRET) studies (5,8,9) on the isolated ligand binding domain of the GluR2 subunit (GluR2-S1S2) have provided insight into the role of specific ligand-protein interactions in mediating AMPA receptor activation. By using these techniques to study activation by the three ligands kainate, AMPA, and glutamate on wild type and mutant proteins, which provide a wide spectrum of activations, a correlation was developed between the changes at specific ligand-protein interactions and extent of activation of the channel. These studies suggest that the strength of the interaction at the α-amine group correlates in most cases to the § Address correspondence to: Vasanthi Jayaraman, Center for Membrane Biology, Department of Biochemistry and Molecular Biology, University of Texas Health Science Center, 6431 Fannin St., Houston, Texas, 77030; (5,6). However, it should be noted that these correlations depended heavily on conclusions from the partial agonist kainate, which is inherently different in structure compared to glutamate and AMPA because it...

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“…The resultant transmembrane (TM) current initiates a regenerative electrical signal called an action potential, but the channels quickly become unresponsive during sustained exposure to glutamate. A recent paper by Armstrong et al (1) provides the first highresolution views of receptor conformations adopted during desensitization.…”

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confidence: 99%

Desensitization at the Interface

Howe

2006

ACS Chem. Biol.

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Normal brain function requires the faithful transmission and integration of information on a timescale of milliseconds, and this rapid signaling is mediated by cell membrane receptors that are ligand-gated ion channels. Fast excitatory transmission occurs when synaptically released glutamate opens channels in neighboring neurons, but these channels desensitize rapidly during sustained high-frequency firing. Recent structural data have begun to provide important insights into the molecular mechanisms that underlie channel activation and desensitization.

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Measurement of Conformational Changes accompanying Desensitization in an Ionotropic Glutamate Receptor

Cited by 204 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

Chemical Interplay in the Mechanism of Partial Agonist Activation in α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid Receptors

Desensitization at the Interface

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