RT Journal Article SR Electronic T1 Permeant Ion Effects on External Mg2+ Block of NR1/2D NMDA Receptors JF The Journal of Neuroscience JO J. Neurosci. FD Society for Neuroscience SP 10899 OP 10910 DO 10.1523/JNEUROSCI.3453-06.2006 VO 26 IS 42 A1 Anqi Qian A1 Jon W. Johnson YR 2006 UL http://www.jneurosci.org/content/26/42/10899.abstract AB Voltage-dependent channel block by external Mg2+ (Mgo2+) of NMDA receptors is an essential determinant of synaptic function. The resulting Mgo2+ inhibition of NMDA responses depends strongly on receptor subunit composition: NR1/2A and NR1/2B receptors are more strongly inhibited by Mgo2+ than are NR1/2C or NR1/2D receptors. Previous work showed that permeant ions have profound effects on Mgo2+ block of NMDA receptors composed of NR1, NR2A, and NR2B subunits. Whether permeant ions affect Mgo2+ inhibition of NR1/2C or NR1/2D receptors is unknown. We investigated the effects of permeant ions on Mgo2+ 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 Mgo2+ IC50 and in the apparent Mgo2+ unblocking rate, and increase in the apparent Mgo2+ blocking rate (k+,app) of NR1/2D receptors. Lowering external [Na+] caused modest voltage-dependent changes in the Mgo2+ 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 Mgo2+ entry into the channel. Occupation of an internal permeant ion binding site prevents Mgo2+ permeation and accelerates Mgo2+ unblock to the external solution. We conclude that variations in permeant ion site properties shape the NR2 subunit dependence of Mgo2+ block. Furthermore, the external channel entrance varies little among NMDA receptor subtypes. Differences in the Mgo2+ blocking site, and particularly in the selectivity filter and internal channel entrance, are principally responsible for the subunit dependence of Mgo2+ block.