Different Gating Mechanisms in Glutamate Receptor and K<sup>+</sup>Channels

Sobolevsky, Alexander I.; Yelshansky, Maria V.; Wollmuth, Lonnie P.

doi:10.1523/jneurosci.23-20-07559.2003

Cited by 55 publications

(96 citation statements)

References 42 publications

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“…Previous results have suggested that the M3-S2 linker has a different conformation in the open and closed states (Sobolevsky et al, 2003). The accessibility pattern shown in Figure 7B suggests that the nonconducting closed and desensitized states of the AMPAR channel are also structurally different at the linker level.…”

Section: Different Structures Of the M3-s2 Linker In The Closed And Dmentioning

confidence: 72%

“…On the other hand, substitutions of these residues in AMPARs (Jatzke et al, 2003) and of homologous positions in the NMDAR NR1 subunit (Watanabe et al, 2002) affect Ca 2ϩ permeation, suggesting that they are associated with the ion conduction pathway. Nevertheless, ER is positioned four amino acid residues external to SYTANLAAF, a motif forming the most extracellular part of the channel (Sobolevsky et al, 2003). We therefore refer to the location of ER between the ligandbinding domain and the ion channel as the M3-S2 linker.…”

Section: Charged Residues In the M3-s2 Linker Influence Channel Gatingmentioning

confidence: 99%

“…One end of M3-S2 is connected to the S2 domain, a part of the ligand-binding domain with the structure solved by crystallography (Armstrong et al, 1998;Armstrong and Gouaux, 2000). On the other side, M3-S2 is connected to the M3 segment that, based on sidedness of accessibility to MTS reagents, is ␣-helical (Sobolevsky et al, 2003). The secondary structure of the M3-S2 linker itself may be difficult to infer from the pattern of accessibility because this region is outside the transmembrane portion of GluR and hence may be water-accessible on all sides.…”

Section: Different Structures Of the M3-s2 Linker In The Closed And Dmentioning

confidence: 99%

“…1 A). All four hydrophobic segments (M1-M4) apparently contribute to the ion channel (Kuner et al, , 2001Beck et al, 1999), with M3 representing the major structural element lining the pore and involved in channel opening and closure (Kohda et al, 2000;Jones et al, 2002;Sobolevsky et al, 2002Sobolevsky et al, , 2003. Accordingly, the linker between M3 and the ligandbinding domain, the M3-S2 linker, transfers the conformational changes in the ligand-binding domain to M3, but its structural and functional contribution to gating in non-NMDARs is unknown.…”

Section: Introductionmentioning

confidence: 99%

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Block of AMPA Receptor Desensitization by a Point Mutation outside the Ligand-Binding Domain

Yelshansky¹,

Sobolevsky²,

Jatzke³

et al. 2004

J. Neurosci.

101

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Desensitization of ionotropic glutamate receptors (GluRs), specifically the AMPA receptor subtype, shapes the postsynaptic response at certain synapses in the brain. All known mechanisms that alter desensitization, either pharmacological or mutational, are associated with the ligand-binding domain. Here we report that substitution of a conserved positively charged arginine (R) with a negatively charged glutamate in the linker between the pore-forming M3 segment and the S2 lobe, a region outside the ligand-binding domain, blocks desensitization in homomeric AMPA receptors composed of GluR-B i subunits. A charge-reversing substitution of a glutamate adjacent to this conserved R enhanced desensitization, consistent with these effects attributable to electrostatics. Homologous substitutions of the conserved R in GluR-B o , GluR-A i and the kainate receptor GluR-6 subunits produced comparable but less visible effects on desensitization. Subunit specificity was also apparent for accessibility of substituted cysteines in the M3-S2 linker, suggesting that this part of the channel is not structurally identical in different GluRs. Additionally, reactivity with a sulfhydryl-specific reagent was state dependent, suggesting that the conformations of the nonconducting closed and desensitized states are different at the level of the M3-S2 linker. Our results therefore represent the first identification of elements outside the ligand-binding domain affecting desensitization in non-NMDA receptor channels and suggest that electrostatic interactions involving charged residues in the M3-S2 linker influence channel gating in a subunit-and subtype-specific manner.

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Section: Different Structures Of the M3-s2 Linker In The Closed And Dmentioning

confidence: 72%

Section: Charged Residues In the M3-s2 Linker Influence Channel Gatingmentioning

confidence: 99%

Section: Different Structures Of the M3-s2 Linker In The Closed And Dmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Block of AMPA Receptor Desensitization by a Point Mutation outside the Ligand-Binding Domain

Yelshansky¹,

Sobolevsky²,

Jatzke³

et al. 2004

J. Neurosci.

101

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“…and glutamate receptors are thought to share a common transmembrane architecture (Wood et al, 1995;Kuner et al, 2003;Sobolevsky et al, 2003), suggesting that the mechanism by which protons modulate these channels could be similar. Schulte et al (2001) have suggested that a close interaction exists between a proton sensor outside the pore and gating of Kir channels (Ruppersberg, 2000).…”

Section: Structural Implicationsmentioning

confidence: 99%

Protons Trap NR1/NR2B NMDA Receptors in a Nonconducting State

Banke¹,

Dravid²,

Traynelis³

2005

J. Neurosci.

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NMDA receptors are highly expressed in the CNS and are involved in excitatory synaptic transmission, as well as synaptic plasticity. Given that overstimulation of NMDA receptors can cause cell death, it is not surprising that these channels are under tight control by a series of inhibitory extracellular ions, including zinc, magnesium, and H ϩ . We studied the inhibition by extracellular protons of recombinant NMDA receptor NR1/NR2B single-channel and macroscopic responses in transiently transfected human embryonic kidney HEK 293 cells using patch-clamp techniques. We report that proton inhibition proceeds identically in the absence or presence of agonist, which rules out the possibility that protonation inhibits receptors by altering coagonist binding. The response of macroscopic currents in excised patches to rapid jumps in pH was used to estimate the microscopic association and dissociation rates for protons, which were 1.4 ϫ 10 9 M Ϫ1 sec Ϫ1 and 110 -196 sec Ϫ1 , respectively (K d corresponds to pH 7.2). Protons reduce the open probability without altering the time course of desensitization or deactivation. Protons appear to slow at least one time constant describing the intra-activation shut-time histogram and modestly reduce channel open time, which we interpret to reflect a reduction in the overall channel activation rate and possible proton-induced termination of openings. This is consistent with a modest proton-dependent slowing of the macroscopic response rise time. From these data, we propose a physical model of proton inhibition that can describe macroscopic and single-channel properties of NMDA receptor function over a range of pH values.

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Modeling of peptides connecting the ligand‐binding and transmembrane domains in the GluR2 glutamate receptor

Speranskiy

Kurnikova

2009

Proteins

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Ligand-gated Glutamate receptors (GluR) mediate synaptic signals in the nervous system. Ionotropic GluRs of AMPA type, the subject of the present study, are tetrameric assemblies of monomer subunits, each of which is constructed in a modular fashion from functional subdomains. The extracellular ligand binding domain (LBD) changes its conformation upon binding of an agonist ligand followed by opening of a transmembrane (TM) ion channel. Peptides connecting the LBD and TM domains facilitate gating of the channel, and their structure and composition are important for the receptor functioning. In this study we used Replica Exchange Molecular Dynamics (REMD) simulations to model S1M1 and S2M3 connecting peptides of the GluR2 receptor in two implicit solvents, water and interfacial water/lipid medium characterized by lower polarity. Propensity of these peptides to form helical structures was analyzed using helicity measure derived from the free energy of the simulated ensembles of structures. The S1M1 and S2M3 connecting peptides were not helical in our simulations in both dielectric environments in the absence of the rest of the protein. The structures of the LBD fragment with known high resolution α-helical structure and of the TM3 helix were successfully predicted in the simulations, which in part validate our results. The S2M3 peptide which is important in gating formed a welldefined coil structure and salt-bridges with the S2 domain. The S1M1 peptide formed a loop structure via formation of internal salt-bridges. Potential implications of these structures on function of the receptor are discussed.

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Different Gating Mechanisms in Glutamate Receptor and K⁺Channels

Cited by 55 publications

References 42 publications

Block of AMPA Receptor Desensitization by a Point Mutation outside the Ligand-Binding Domain

Block of AMPA Receptor Desensitization by a Point Mutation outside the Ligand-Binding Domain

Protons Trap NR1/NR2B NMDA Receptors in a Nonconducting State

Modeling of peptides connecting the ligand‐binding and transmembrane domains in the GluR2 glutamate receptor

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Different Gating Mechanisms in Glutamate Receptor and K+Channels

Cited by 55 publications

References 42 publications

Block of AMPA Receptor Desensitization by a Point Mutation outside the Ligand-Binding Domain

Block of AMPA Receptor Desensitization by a Point Mutation outside the Ligand-Binding Domain

Protons Trap NR1/NR2B NMDA Receptors in a Nonconducting State

Modeling of peptides connecting the ligand‐binding and transmembrane domains in the GluR2 glutamate receptor

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Product

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Different Gating Mechanisms in Glutamate Receptor and K⁺Channels