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Mechanisms of NMDA receptor inhibition by memantine and ketamine

Glasgow, Nathan G (2016) Mechanisms of NMDA receptor inhibition by memantine and ketamine. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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NMDA receptors (NMDARs), a subfamily of ionotropic glutamate receptors, have unique biophysical properties including high permeability to Ca2+. Activation of NMDARs increases the concentration of intracellular Ca2+ that can activate a vast array of signaling pathways. NMDARs are necessary for many processes including synaptic plasticity, dendritic integration, and cell survival. Aberrant NMDAR activation is implicated in many central nervous system disorders including neurodegenerative disorders, neuronal loss following ischemia, and neuropsychiatric disorders. Hope that NMDARs may serve as useful therapeutic targets is bolstered by the clinical success of two NMDAR antagonists, memantine and ketamine. Memantine and ketamine act as open channel blockers of the NMDAR-associated ion channel, and exhibit similar IC50 values and kinetics. Memantine is approved for treatment of Alzheimer's disease and shows promise in treatments of Huntington's disease, and ischemia. Ketamine was initially approved for use as a general anesthetic, but has recently shown efficacy in treatment of depression and of pain. Notably, memantine is not effective in treatment of depression or pain. In addition, memantine is well tolerated, whereas ketamine induces psychotomimetic side effects. The basis for the divergent clinical profiles of memantine and ketamine is not clear. One recently-proposed hypothesis is that memantine and ketamine inhibit overlapping but distinct subpopulations of NMDARs. However, mechanisms underlying inhibition of distinct NMDAR subpopulations by memantine or by ketamine are not fully understood. We therefore examined and compared mechanisms of inhibition by memantine and by ketamine. We also describe a novel fast perfusion system optimized for brief synaptic-like glutamate applications to lifted cells. We found that: (1) inhibition by memantine and ketamine exhibit differential dependence on duration of receptor activation and on NMDAR subtype; (2) the dependence of memantine inhibition on duration of NMDAR activation results from stabilization of a Ca2+-dependent desensitized state; (3) the endogenous NMDAR open channel blocker Mg2+ slows the binding kinetics of both memantine and ketamine, and, unexpectedly, speeds recovery from memantine inhibition; (4) although inhibition by memantine was thought to be mediated by only the charged form of memantine, the uncharged form of memantine also binds to and inhibits NMDARs, and exhibits surprisingly slow unbinding kinetics.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Glasgow, Nathan Gngg1@pitt.eduNGG1
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairJohnson, Jon Wjjohnson@pitt.eduJJOHNSON
Committee MemberMeriney, Stephen Dmeriney@pitt.eduMERINEY
Committee MemberOswald, Anne-Marie Mamoswald@pitt.eduAMOSWALD
Committee MemberAizenman, Eliasredox@pitt.eduREDOX
Committee MemberGold, Michael Smsg22@pitt.eduMSG22
Committee MemberTraynelis, Stephen Fstrayne@emory.eduNA
Date: 29 September 2016
Date Type: Publication
Defense Date: 21 April 2016
Approval Date: 29 September 2016
Submission Date: 7 June 2016
Access Restriction: 1 year -- Restrict access to University of Pittsburgh for a period of 1 year.
Number of Pages: 241
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: NMDA receptor; channel block; memantine; ketamine; desensitization; inactivation
Date Deposited: 30 Sep 2016 01:16
Last Modified: 29 Sep 2017 05:15


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