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DC Field | Value | Language |
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dc.contributor.author | Lin, Ying | |
dc.date.accessioned | 2018-07-12T17:32:49Z | |
dc.date.available | 2018-07-12T17:32:49Z | |
dc.date.issued | 2003 | |
dc.identifier.citation | Source: Dissertation Abstracts International, Volume: 64-08, Section: B, page: 3691.;Advisors: R. Suzanne Zukin. | |
dc.identifier.uri | https://ezproxy.yu.edu/login?url=http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqm&rft_dat=xri:pqdiss:3102825 | |
dc.identifier.uri | https://hdl.handle.net/20.500.12202/649 | |
dc.description.abstract | NMDA (N-methyl-D-aspartate) receptors (NMDARs) are glutamate-gated ion channels that mediate synaptic transmission at excitatory synapses of the brain. Synaptic NMDARs are localized to p&barbelow;osts&barbelow;ynaptic d&barbelow;ensities (PSDs). The overall objective of this thesis research is to elucidate the molecular mechanisms by which PSD-95 regulates NMDAR gating and trafficking and modulation by protein kinases. To achieve this purpose, experiments involving patch-clamp and whole-cell recording, biotinylation western-blot analysis of cell surface proteins, immmunofluorescence and site-directed mutagenesis were carried out on Xenopus oocytes and HEK-293 cells expressing recombinant NR1/NR2A NMDARs. We chose NR1/NR2A receptors because they are the predominant NMDAR subtype expressed at mature excitatory synapses. Recombinant receptor systems provide expression of a homogenous population of NMDARs and geometric simplicity.;The first part of my thesis research focuses on regulation of NMDAR gating and trafficking by PSD-95. Single-channel recording from outside-out patches excised from Xenopus oocytes expressing NR1/NR2A receptors in the presence and absence of PSD-95 show that PSD-95 increases NMDA channel npo (the number of functional channel times open probability), with little or no change in single channel conductance, reversal potential or mean open time. I demonstrate that PSD-95 increases the number of functional NMDA channels. Moreover, PSD-95 increases the rate of decay of the NMDA-elicited current in the presence of MK-801, indicating an increase in the opening rate of NMDA channels. Removal of the PDZ binding motif in the NR2A subunit abolished the effects of PSD-95 on NMDA-elicited current, NMDAR surface expression and receptor internalization. These data suggest that physical interaction of NMDARs with PSD-95 is critical for PSD-95 regulation of NMDAR function and trafficking.;The second part of my thesis research investigates the molecular mechanism whereby PSD-95 reduces PKC potentiation of NMDA receptors. Truncation experiments indicate that the C-terminal domain of the NR2, rather than the NR1 subunit is responsible for PSD-95 actions. PSD-95 blocks PKC potentiation by occlusion of PKC-induced delivery of new NMDA channels to the plasma membrane and increase of NMDA channel opening rate. These mechanisms may be relevant to synaptic plasticity. (Abstract shortened by UMI.). | |
dc.publisher | ProQuest Dissertations & Theses | |
dc.subject | Neurosciences. | |
dc.title | Regulation of NMDA receptor gating and trafficking by PSD-95 | |
dc.type | Dissertation | |
Appears in Collections: | Albert Einstein College of Medicine: Doctoral Dissertations |
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