Abstract
SummaryIonotropic glutamate receptors (iGluRs) harbor two extracellular domains: the membrane-proximal ligand-binding domain (LBD) and the distal N-terminal domain (NTD). These are involved in signal sensing: the LBD binds L-glutamate, which activates the receptor channel. Ligand binding to the NTD modulates channel function in the NMDA receptor subfamily of iGluRs, which has not been observed for the AMPAR subfamily to date. Structural data suggest that AMPAR NTDs are packed into tight dimers and have lost their signaling potential. Here, we assess NTD dynamics from both subfamilies, using a variety of computational tools. We describe the conformational motions that underly NMDAR NTD allosteric signaling. Unexpectedly, AMPAR NTDs are capable of undergoing similar dynamics; although dimerization imposes restrictions, the two subfamilies sample similar, interconvertible conformational subspaces. Finally, we solve the crystal structure of AMPAR GluA4 NTD, and combined with molecular dynamics simulations, we characterize regions pivotal for an as-yet-unexplored dynamic spectrum of AMPAR NTDs.
Highlights
Ionotropic glutamate receptors encompass a family of tetrameric glutamate-gated cation channels that mediate the majority of excitatory neurotransmission in the vertebrate central nervous system
We first solved the structure of the remaining GluA4 N-terminal domain (NTD) to facilitate a comprehensive analysis of this domain across the amino-3-hydroxy-5-methyl-4-isozazolepropionic acid receptors (AMPARs) subfamily
Effect of Dimeric Packing on the Intrinsic Dynamics of AMPAR and N-methyl-Daspartate receptors (NMDARs) NTD Monomers Because AMPAR- but not NMDAR-NTDs assemble into stable homodimers (Clayton et al, 2009; Jin et al, 2009; Rossmann et al, 2011; Zhao et al, 2012), we evaluated the changes in dynamics upon NTD dimerization, using a perturbation method (Zheng and Brooks, 2005; Ming and Wall, 2005b), which facilitates assessing the effect of environment on the dynamics of examined systems
Summary
Ionotropic glutamate receptors (iGluRs) encompass a family of tetrameric glutamate-gated cation channels that mediate the majority of excitatory neurotransmission in the vertebrate central nervous system. Their operation underlies higher-order cognitive functions (Traynelis et al, 2010). The iGluR family harbors three major subfamilies: a-amino-3-hydroxy-5-methyl-4-isozazolepropionic acid receptors (AMPARs), kainate receptors (KRs), and N-methyl-Daspartate receptors (NMDARs). Sequence similarity and structural data suggest a shared architecture between these subfamilies: an extracellular domain (ECD), a transmembrane domain (TMD), and an intracellular carboxyl-terminal domain that mediates trafficking and anchorage at synaptic sites (Traynelis et al, 2010; Dingledine, 2010). The ECD consists of a distal N-terminal domain (NTD) and ligand-binding domain (LBD)
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