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Molecular Mechanisms of Ionotropic Glutamate Receptor Assembly

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dc.contributor.advisor Wollmuth, Lonnie P en_US
dc.contributor.author Salussolia, Catherine Lourdes en_US
dc.contributor.other Department of Neuroscience en_US
dc.date.accessioned 2013-05-22T17:35:32Z
dc.date.accessioned 2015-04-24T14:47:25Z
dc.date.available 2013-05-22T17:35:32Z
dc.date.available 2015-04-24T14:47:25Z
dc.date.issued 2012-05-01
dc.identifier Salussolia_grad.sunysb_0771E_10917 en_US
dc.identifier.uri http://hdl.handle.net/1951/59848 en_US
dc.identifier.uri http://hdl.handle.net/11401/71398 en_US
dc.description 161 pg. en_US
dc.description.abstract Abstract of the Dissertation Molecular Mechanisms of Ionotropic Glutamate Receptor Assembly by Catherine Lourdes Salussolia Doctor of Philosophy in Neuroscience Stony Brook University 2012 Fast excitatory neurotransmission mediated by the neurotransmitter glutamate via ionotropic glutamate receptors (iGluRs) is essential to central nervous system function. Perturbations in glutamatergic signaling - including alterations in iGluR membrane expression - have been implicated in numerous nervous system diseases including psychiatric, developmental, acute excitotoxic and chronic neurodegenerative disorders. iGluR biogenesis is a complex process that requires many coordinated events - biosynthesis, folding, oligomerization of subunits (dimerization and tetramerization), post-translational modification, and insertion into the plasma membrane. iGluR subtypes form preferential (AMPA, kainate) or obligate (NMDA) heterotetramers that assemble as a dimer of dimers to yield functional receptors. Functional NMDA receptors (NMDARs) are obligate heteromers composed of two GluN1 and typically two GluN2 subunits; however, the arrangement of subunits in functional tetrameric complexes - whether identical subunits are positioned adjacent to (N1/N1/N2/N2) or diagonal to (N1/N2/N1/N2) one another - was controversial. In my first project, I addressed the arrangement of subunits in functional NMDARs by utilizing the recent insight that individual subunits within a homotetrameric AMPA receptor adopt two distinct conformations - termed A/C and B/D. Using cysteine mutagenesis, immunoblots, and functional assays, I showed that GluN subunits adopt distinct subunit-specific conformations with the GluN1 and GluN2 subunits approximating the A/C and B/D conformations, respectively, demonstrating that GluN subunits are positioned in a N1/N2/N1/N2 arrangement. In contrast to prokaryotic iGluR subunits, all eukaryotic iGluRs have an additional transmembrane segment, the M4 segment, located C-terminal to the ion channel core (M1-M3). Surprisingly, in the AMPAR structure, the M4 segment of one subunit was associated with the ion channel core of an adjacent subunit. My second project addressed the functional implications of the M4 transmembrane segment. I showed that disruption of a specific face of M4 that is closely apposed to the adjacent M1 and M3 segments in the crystal structure results in a loss of AMPAR surface expression. These data suggest that the M4/ion channel core interaction is necessary for iGluR expression and may represent a novel mechanism regulating iGluR assembly. Overall my work provides novel insights into the biogenic mechanisms regulating the structure/function of iGluRs and suggests possible therapeutic targets for modulating dysfunctional glutamatergic activity. en_US
dc.description.sponsorship This work is sponsored by the Stony Brook University Graduate School in compliance with the requirements for completion of degree. en_US
dc.format Monograph en_US
dc.format.medium Electronic Resource en_US
dc.language.iso en_US en_US
dc.publisher The Graduate School, Stony Brook University: Stony Brook, NY. en_US
dc.subject.lcsh Neurosciences en_US
dc.subject.other AMPA receptor, Biogenesis, Glutamate Receptor, NMDA receptor en_US
dc.title Molecular Mechanisms of Ionotropic Glutamate Receptor Assembly en_US
dc.type Dissertation en_US
dc.mimetype Application/PDF en_US
dc.contributor.committeemember Kernan, Maurice en_US
dc.contributor.committeemember Furukawa, Hiro en_US
dc.contributor.committeemember Talmage, David en_US
dc.contributor.committeemember Akabas, Myles en_US


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