{"@context":"http://iiif.io/api/presentation/2/context.json","@id":"https://repo.library.stonybrook.edu/cantaloupe/iiif/2/manifest.json","@type":"sc:Manifest","label":"The Mechanisms of NMDA Receptor Activation","metadata":[{"label":"dc.description.sponsorship","value":"This work is sponsored by the Stony Brook University Graduate School in compliance with the requirements for completion of degree."},{"label":"dc.format","value":"Monograph"},{"label":"dc.format.medium","value":"Electronic Resource"},{"label":"dc.identifier.uri","value":"http://hdl.handle.net/11401/76580"},{"label":"dc.language.iso","value":"en_US"},{"label":"dc.publisher","value":"The Graduate School, Stony Brook University: Stony Brook, NY."},{"label":"dcterms.abstract","value":"Glutamate-gated ion channels embedded within the neuronal membrane are the primary mediators of fast excitatory synaptic transmission in the central nervous system. The ion channel of these glutamate receptors contains a pore-lining transmembrane M3 helix surrounded by peripheral M1 and M4 helices. In the NMDA receptor (NMDAR), opening of the ion channel pore requires rearrangements of these helical elements, but there is currently no functional model for how this occurs.           To address how agonist binding is transduced into pore opening in NMDARs, we manipulated the coupling between the ligand binding domain (LBD) and the M3 helix of the ion channel by inserting residues in a linker between them. We find that a single residue insertion dramatically attenuates the ability of NMDARs to convert a glutamate transient into a functional response. Computational and thermodynamic analyses suggest that insertions prevent the agonist-bound LBD from effectively pulling on pore lining elements, thereby destabilizing pore opening. Further, this pulling energy is more prominent in the GluN2 subunit. We conclude that an efficient NMDAR-mediated synaptic response relies on a mechanical coupling between the LBD and the ion channel.           We then sought to understand how the peripheral elements contribute to pore opening. We approached this question by constraining the relative movements of the linkers that connect these helices to the LBD using engineered cross-links, either within or between subunits. Constraining the peripheral linkers in any manner dramatically curtailed channel opening, highlighting the requirement for rearrangements of these peripheral structural elements for efficient gating to occur.  However, the magnitude of this gating effect was most dramatic when the constraint was between subunits. Our results suggest an asynchrony in the displacement of the peripheral elements during the conformational and energetic changes leading to pore opening. Thus, the conformational changes induced by agonist binding in NMDA receptors converge asynchronously to permit pore opening."},{"label":"dcterms.available","value":"2017-09-20T16:50:42Z"},{"label":"dcterms.contributor","value":"Wollmuth, Lonnie P"},{"label":"dcterms.creator","value":"Kazi, Rashek"},{"label":"dcterms.dateAccepted","value":"2017-09-20T16:50:42Z"},{"label":"dcterms.dateSubmitted","value":"2017-09-20T16:50:42Z"},{"label":"dcterms.description","value":"Department of Neuroscience."},{"label":"dcterms.extent","value":"180 pg."},{"label":"dcterms.format","value":"Monograph"},{"label":"dcterms.identifier","value":"http://hdl.handle.net/11401/76580"},{"label":"dcterms.issued","value":"2014-12-01"},{"label":"dcterms.language","value":"en_US"},{"label":"dcterms.provenance","value":"Made available in DSpace on 2017-09-20T16:50:42Z (GMT). No. of bitstreams: 1\nKazi_grad.sunysb_0771E_11788.pdf: 5935879 bytes, checksum: f381db5125205c6afe3a13990fde1713 (MD5)\n  Previous issue date:    1"},{"label":"dcterms.publisher","value":"The Graduate School, Stony Brook University: Stony Brook, NY."},{"label":"dcterms.subject","value":"Allostery, Glutamate, Ion Channel, NMDA, Single Channel, Thermodynamics"},{"label":"dcterms.title","value":"The Mechanisms of NMDA Receptor Activation"},{"label":"dcterms.type","value":"Dissertation"},{"label":"dc.type","value":"Dissertation"}],"description":"This manifest was generated dynamically","viewingDirection":"left-to-right","sequences":[{"@type":"sc:Sequence","canvases":[{"@id":"https://repo.library.stonybrook.edu/cantaloupe/iiif/2/canvas/page-1.json","@type":"sc:Canvas","label":"Page 1","height":1650,"width":1275,"images":[{"@type":"oa:Annotation","motivation":"sc:painting","resource":{"@id":"https://repo.library.stonybrook.edu/cantaloupe/iiif/2/98%2F89%2F57%2F9889571844051593454108850456416615938/full/full/0/default.jpg","@type":"dctypes:Image","format":"image/jpeg","height":1650,"width":1275,"service":{"@context":"http://iiif.io/api/image/2/context.json","@id":"https://repo.library.stonybrook.edu/cantaloupe/iiif/2/98%2F89%2F57%2F9889571844051593454108850456416615938","profile":"http://iiif.io/api/image/2/level2.json"}},"on":"https://repo.library.stonybrook.edu/cantaloupe/iiif/2/canvas/page-1.json"}]}]}]}