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Slow Mg²⁺ unblock and inherent voltage dependence of NMDA receptors

Clarke, Richard J (2006) Slow Mg²⁺ unblock and inherent voltage dependence of NMDA receptors. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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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.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Clarke, Richard
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairJohnson, Jonjohnson@bns.pitt.eduJJOHNSON
Committee MemberAizenman, Eliasredox@pitt.eduREDOX
Committee MemberBarrionuevo, Germángerman@bns.pitt.eduGERMAN
Committee MemberUrban,
Committee MemberDrain, Peterdrain@pitt.eduDRAIN
Committee MemberTraynelis,
Date: 20 September 2006
Date Type: Completion
Defense Date: 17 July 2006
Approval Date: 20 September 2006
Submission Date: 15 August 2006
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
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; whole-cell patch clamp; ion channels; synaptic transmission
Other ID:, etd-08152006-152413
Date Deposited: 10 Nov 2011 19:59
Last Modified: 15 Nov 2016 13:49


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