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The Journal of Neuroscience, October 18, 2006, 26(42):10899-10910; doi:10.1523/JNEUROSCI.3453-06.2006

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Cellular/Molecular
Permeant Ion Effects on External Mg²⁺ Block of NR1/2D NMDA Receptors

Anqi Qian and Jon W. Johnson

Department of Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania 15260

Correspondence should be addressed to Jon W. Johnson, Department of Neuroscience, A410 Langley Hall, University of Pittsburgh, Pittsburgh, PA 15260. Email: johnson{at}bns.pitt.edu

Voltage-dependent channel block by external Mg²⁺ (Mg_o²⁺) of NMDA receptors is an essential determinant of synaptic function. The resulting Mg_o²⁺ inhibition of NMDA responses depends strongly on receptor subunit composition: NR1/2A and NR1/2B receptors are more strongly inhibited by Mg_o²⁺ than are NR1/2C or NR1/2D receptors. Previous work showed that permeant ions have profound effects on Mg_o²⁺ block of NMDA receptors composed of NR1, NR2A, and NR2B subunits. Whether permeant ions affect Mg_o²⁺ inhibition of NR1/2C or NR1/2D receptors is unknown. We investigated the effects of permeant ions on Mg_o²⁺ block of NR1/2D receptors by integrating results from whole-cell recordings, single-channel recordings, and kinetic modeling. Lowering internal [Cs⁺] caused a voltage-dependent decrease in the Mg_o²⁺ IC₅₀ and in the apparent Mg_o²⁺ unblocking rate, and increase in the apparent Mg_o²⁺ blocking rate (k_+,app) of NR1/2D receptors. Lowering external [Na⁺] caused modest voltage-dependent changes in the Mg_o²⁺ IC₅₀ and k_+,app. These data can be explained by a kinetic model in which occupation of either of two external permeant ion binding sites prevents Mg_o²⁺ entry into the channel. Occupation of an internal permeant ion binding site prevents Mg_o²⁺ permeation and accelerates Mg_o²⁺ unblock to the external solution. We conclude that variations in permeant ion site properties shape the NR2 subunit dependence of Mg_o²⁺ block. Furthermore, the external channel entrance varies little among NMDA receptor subtypes. Differences in the Mg_o²⁺ blocking site, and particularly in the selectivity filter and internal channel entrance, are principally responsible for the subunit dependence of Mg_o²⁺ block.

Key words: NMDA receptors; glutamate receptors; channel block; single channel; magnesium; inhibition

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Received Aug. 9, 2006; revised Sept. 7, 2006; accepted Sept. 8, 2006.

Correspondence should be addressed to Jon W. Johnson, Department of Neuroscience, A410 Langley Hall, University of Pittsburgh, Pittsburgh, PA 15260. Email: johnson{at}bns.pitt.edu

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