Journal
NEUROSCIENCE LETTERS
Volume 700, Issue -, Pages 22-29Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.neulet.2018.02.050
Keywords
Ionotropic glutamate receptors; AMPA and NMDA receptors; Simulations; Molecular dynamics; Elastic network models; Allosteric interactions; Activation mechanism; Desensitization
Categories
Funding
- National Institutes of Health [P41 GM103712, R01 GM099738, P30 DA035778]
- Medical Research Council [MC_U105174197]
- Biotechnology and Biological Sciences Research Council [BB/N002113/1]
- MRC [MC_U105174197] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/N002113/1] Funding Source: researchfish
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Ionotropic glutamate receptors (iGluRs) are ligand-gated ion channels that are key players in synaptic transmission and plasticity. They are composed of four subunits, each containing four functional domains, the quaternary packing and collective structural dynamics of which are important determinants of their molecular mechanism of function. With the explosion of structural studies on different members of the family, including the structures of activated open channels, the mechanisms of action of these central signaling machines are now being elucidated. We review the current state of computational studies on two major members of the family, AMPA and NMDA receptors, with focus on molecular simulations and elastic network model analyses that have provided insights into the coupled movements of extracellular and transmembrane domains. We describe the newly emerging mechanisms of activation, allosteric signaling and desensitization, as mainly a selective triggering of pre-existing soft motions, as deduced from computational models and analyses that leverage structural data on intact AMPA and NMDA receptors in different states.
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