A Conserved Mechanism for Gating in an Ionotropic Glutamate Receptor

Moore, Bryn; Mirshahi, Uyenlinh L.; Ebersole, Tonya L.; Mirshahi, Tooraj

doi:10.1074/jbc.m113.465187

Cited by 9 publications

(10 citation statements)

References 34 publications

(46 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This weakening of desensitization was redox-independent, suggesting an electrostatic and/or steric effect of this mutation on GluA2 desensitization 29 30 . Small but significant reduction of desensitization was also detected for the A621C mutant, reminiscent of a stronger effect on desensitization previously observed for the A621G mutant 31 . A621 is a part of the highly conserved SYTANL A AF motif 32 apparently involved in iGluR gating 31 33 34 35 36 37 .…”

Section: Resultssupporting

confidence: 72%

Probing Intersubunit Interfaces in AMPA-subtype Ionotropic Glutamate Receptors

Yelshanskaya

Saotome

Singh

et al. 2016

Sci Rep

View full text Add to dashboard Cite

AMPA subtype ionotropic glutamate receptors (iGluRs) mediate the majority of fast neurotransmission across excitatory synapses in the central nervous system. Each AMPA receptor is composed of four multi-domain subunits that are organized into layers of two amino-terminal domain (ATD) dimers, two ligand-binding domain (LBD) dimers, transmembrane domains and carboxy-terminal domains. We introduced cysteine substitutions at the intersubunit interfaces of AMPA receptor subunit GluA2 and confirmed substituted cysteine crosslink formation by SDS-PAGE. The functional consequence of intersubunit crosslinks was assessed by recording GluA2-mediated currents in reducing and non-reducing conditions. Strong redox-dependent changes in GluA2-mediated currents were observed for cysteine substitutions at the LBD dimer-dimer interface but not at the ATD dimer-dimer interface. We conclude that during gating, LBD dimers undergo significant relative displacement, while ATD dimers either maintain their relative positioning, or their relative displacement has no appreciable effect on AMPA receptor function.

show abstract

Section: Resultssupporting

confidence: 72%

Probing Intersubunit Interfaces in AMPA-subtype Ionotropic Glutamate Receptors

Yelshanskaya

Saotome

Singh

et al. 2016

Sci Rep

View full text Add to dashboard Cite

show abstract

“…This region bears high structural homology to the corresponding region in K + channels (Fig. 3B) and similarly was proposed to serve as an activation gate (Chang and Kuo, 2008;Moore et al 2013). Whether the extended portion of M2, which defines iGluR permeation and channel block but is apparently disordered in the GluA2 structure, also contributes to the activation gate (Sobolevsky et al 2002) remains uncertain.…”

Section: Gatingmentioning

confidence: 88%

Structure and gating of tetrameric glutamate receptors

Sobolevsky

2013

The Journal of Physiology

View full text Add to dashboard Cite

Ionotropic glutamate receptors (iGluRs) are ligand-gated ion channels that open their ion-conducting pores in response to the binding of agonist glutamate. In recent years, significant progress has been achieved in studies of iGluRs by determining numerous structures of isolated water-soluble ligand-binding and amino-terminal domains, as well as solving the first crystal structure of the full-length AMPA receptor in the closed, antagonist-bound state. These structural data combined with electrophysiological and fluorescence recordings, biochemical experiments, mutagenesis and molecular dynamics simulations have greatly improved our understanding of iGluR assembly, activation and desensitization processes. This article reviews the recent structural and functional advances in the iGluR field and summarizes them in a simplified model of full-length iGluR gating.

show abstract

“…The M3 helices are connected by linkers to the LBDs for activation gating. Mutations in M3 influence agonist efficacy, modulate the function of partial agonists, and impact on desensitization kinetics (Moore et al, 2013;Taverna et al, 2000). Recent crystal structures show that noncompetitive antagonists such as GYKI and the anti-epileptic drug perampanel dock in the outer perimeter of the M3 helical bundle to antagonize the channel (Yelshanskaya et al, 2016).…”

Section: The Transmembrane Domain (Tmd)mentioning

confidence: 99%

Structural and Functional Architecture of AMPA-Type Glutamate Receptors and Their Auxiliary Proteins

Greger

Watson

Cull-Candy

2017

Neuron

310

305

View full text Add to dashboard Cite

AMPA receptors (AMPARs) are tetrameric ion channels that together with other ionotropic glutamate receptors (iGluRs), the NMDA and kainate receptors, mediate a majority of excitatory neurotransmission in the central nervous system. Whereas NMDA receptors gate channels with slow kinetics, responsible primarily for generating long-term synaptic potentiation and depression, AMPARs are the main fast transduction elements at synapses and are critical for the expression of plasticity. The kinetic and conductance properties of AMPARs are laid down during their biogenesis and are regulated by post-transcriptional RNA editing, splice variation, post-translational modification, and subunit composition. Furthermore, AMPAR assembly, trafficking, and functional heterogeneity depends on a large repertoire of auxiliary subunits-a feature that is particularly striking for this type of iGluR. Here, we discuss how the subunit structure, stoichiometry, and auxiliary subunits generate a heterogeneous plethora of receptors, each tailored to fulfill a vital role in fast synaptic signaling and plasticity.

show abstract

A Conserved Mechanism for Gating in an Ionotropic Glutamate Receptor

Cited by 9 publications

References 34 publications

Probing Intersubunit Interfaces in AMPA-subtype Ionotropic Glutamate Receptors

Probing Intersubunit Interfaces in AMPA-subtype Ionotropic Glutamate Receptors

Structure and gating of tetrameric glutamate receptors

Structural and Functional Architecture of AMPA-Type Glutamate Receptors and Their Auxiliary Proteins

Contact Info

Product

Resources

About