Wilcox, Madeleine
(2019)
The NMDA Receptor Transmembrane Region in Receptor Function and Inhibition.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
NMDA Receptors (NMDARs) are glutamate- and glycine- gated ion channels present at most excitatory synapses in the mammalian brain. NMDARs are typically composed of four subunits, two GluN1 and two GluN2, which each contain a transmembrane domain (TMD). The TMDs of all four subunits assemble to form the NMDAR ion channel, which opens in response to agonist binding in the extracellular region. The TMD is critical to ion permeation and channel block of NMDARs and small alterations in the TMD can have powerful effects on receptor function. This dissertation discusses work by myself and my coauthors centered around the NMDAR TMD. My coauthors and I first examined the functional effects of mutating a tryptophan residue present at homologous sites in the GluN1 and GluN2 subunit TMDs. We discovered that the conserved tryptophan modulates NMDAR function in a subunit-dependent manner. We next explored the kinetics of NMDAR recovery from inhibition by the therapeutically relevant NMDAR open channel blockers memantine and ketamine. Examination of the kinetics of NMDAR unblock by memantine and ketamine led us to conclude that memantine, but not ketamine, inhibits NMDARs through an additional mechanism that is distinct from traditional open channel block. Building on data from the Johnson lab and others, we characterized a little-studied mechanism of NMDAR inhibition by memantine. Our data suggest that memantine can inhibit NMDARs by entering the plasma membrane and transiting to the NMDAR ion channel through a membrane-to-channel fenestration. We revealed that several NMDAR blockers in addition to memantine inhibit NMDARs through the same fenestration-dependent mechanism.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
25 September 2019 |
| Date Type: |
Publication |
| Defense Date: |
15 May 2019 |
| Approval Date: |
25 September 2019 |
| Submission Date: |
29 July 2019 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Number of Pages: |
193 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
Dietrich School of Arts and Sciences > Neuroscience |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
electrophysiology |
| Date Deposited: |
25 Sep 2019 19:41 |
| Last Modified: |
25 Sep 2019 19:41 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/37225 |
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