N-methyl-D-aspartate (NMDA) receptors are a subtype of ligand-gated ionotropic glutamate receptors that are involved in most fast, excitatory neuronal transmission in the mammalian central nervous system (CNS). NMDA receptor activity is crucial for normal brain function, and NMDA receptor dysregulation has been linked to a number of diseases of the CNS. There are several NMDA receptor subtypes. Each subtype has a unique temporal and spatial expression pattern, suggesting that different subtypes play different physiological roles in the CNS. Here, we have investigated how changes in membrane voltage impact the activity of various NMDA receptor subtypes in the absence and presence of the highly physiologically relevant channel blocker magnesium (Mg²⁺). Mg²⁺ strongly blocks all NMDA receptor subtypes at, and near, typical resting membrane potentials. Only upon depolarization is Mg²⁺ block relieved. We found that, upon depolarization, NMDA receptors containing NR2C or NR2D subunits unblock Mg2+ very rapidly (τ < 1 ms), while Mg²⁺ unblock from NMDA receptors containing the NR2A or NR2B subunit displays a prominent slow component (τ of several ms). We go on to show that the slow component of Mg²⁺ unblock from NR2A and NR2B containing NMDA receptors actually reflects inherent voltage-dependent alterations in NMDA receptor gating. In the absence of Mg²⁺, NR2A and NR2B containing NMDA receptor currents are enhanced upon membrane depolarization. Utilizing data collected in the absence of Mg²⁺, we developed kinetic models of NR2A and NR2B containing NMDA receptors that included inherent voltage sensitivity such that the receptors open more rapidly at positive membrane potentials. The NR2 subunit specific models reproduce experimentally recorded currents during changes in membrane voltage in both the absence and presence of Mg²⁺. The models also reproduce several other previously described voltage-dependent characteristics of the NMDA receptor channel. Inherent voltage dependence further emphasizes the strong link between NMDA receptor activity and neuronal depolarization.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-08152006-152413 |
| Date | 20 September 2006 |
| Creators | Clarke, Richard J |
| Contributors | Peter Drain, Ph.D., Jon Johnson, Ph.D., Nathan Urban, Ph.D., Elias Aizenman, Ph.D., Germán Barrionuevo, M.D., Stephen Traynelis, Ph.D. |
| Publisher | University of Pittsburgh |
| Source Sets | University of Pittsburgh |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.pitt.edu/ETD/available/etd-08152006-152413/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University of Pittsburgh or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
Page generated in 0.1729 seconds