N-methyl-D-aspartate receptors (NMDARs) are glutamate-gated ion channels that play key roles in excitatory synaptic transmission and are involved in numerous neurological disorders as well. The number of neuronal surface NMDARs are not static and can be altered in response to neuronal activity and sensory input. Endocytosis is well known to decrease the number of surface receptors and down-regulate receptor-mediated functions. However, whether a subset of receptor endocytosis regulates the activity of remaining surface (non-internalized) receptors remains unknown. It is shown from this study that the dynamic endocytosis of NMDARs induced by either the activation of group 1 metabotropic glutamate receptors (mGluRs) or the stimulation of the glycine binding site of NMDARs inhibits the activity of remaining surface NMDARs. This effect can be prevented by the modulation of the functional properties of surface NMDARs, for example, inactivating the surface NMDARs by application of the NMDAR antagonist AP5 or blocking Na+ influx. Furthermore, it is shown from this study that the endocytosis of NMDARs enhances the serine phosphorylation of surface NMDAR NR2A subunits. Coincidentally, the inactivation of surface NMDARs or the blockade of Na+ influx produces similar enhancement of serine phosphorylation in NMDARs as well. It is identi ed, by site directed mutagenesis, phosphorylation of NR2A serine 1416 as an essential mechanism in mediating NMDAR endocytosis-induced functional changes in surface receptors. In this study, protein kinase D (PKD/PKCu) is identified to be activated following NMDAR endocytosis, and intracellular application of PKD/PKCu successfully inhibits NMDAR-mediated whole-cell currents. Moreover, the blocking Na+ influx essentially eliminates the NMDAR endocytosis-induced down-regulation of NMDA-evoked whole-cell and synaptic responses. Taken together, the data from this study provide clues on understanding that the reduction of whole-cell responses induced by NMDAR endocytosis is attributed to the inhibition of the activity of remaining surface NMDARs. In addition, the modulation of the functional properties of surface receptors is shown to be an effective way to prevent functional change in surface receptors induced by recptor endocytosis. / A Dissertation submitted to the Department of Biomedical Science in partial fulfillment of the requirements for
the degree of Doctor of Philosophy. / Spring Semester, 2011. / December 10, 2010. / Includes bibliographical references. / Xian-Min Yu, Professor Directing Dissertation; Paul Trombley, University Representative; Charles Ouimet, Committee Member; Choogon Lee, Committee Member.
| Identifer | oai:union.ndltd.org:fsu.edu/oai:fsu.digital.flvc.org:fsu_253269 |
| Contributors | Fang, Xiao-Qian (authoraut), Yu, Xian-Min (professor directing dissertation), Trombley, Paul (university representative), Ouimet, Charles (committee member), Lee, Choogon (committee member), Department of Biomedical Sciences (degree granting department), Florida State University (degree granting institution) |
| Publisher | Florida State University, Florida State University |
| Source Sets | Florida State University |
| Language | English, English |
| Detected Language | English |
| Type | Text, text |
| Format | 1 online resource, computer, application/pdf |
| Rights | This Item is protected by copyright and/or related rights. You are free to use this Item in any way that is permitted by the copyright and related rights legislation that applies to your use. For other uses you need to obtain permission from the rights-holder(s). The copyright in theses and dissertations completed at Florida State University is held by the students who author them. |
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