The trapping block of NMDA receptor channels in acutely isolated rat hippocampal neurones

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Abstract
N-methyl-D-aspartate (NMDA) receptor responses were recorded from acutely isolated rat hippocampal neurones using the whole-cell patch-clamp technique. A rapid perfusion system was used to study the voltage-dependent block of NMDA channels by Mg2+, amantadine (AM) and N-2-(adamantyl)-hexamethylenimine (A-7). Mg2+, AM and A-7-induced stationary blockade of NMDA channels increased with the blocker concentration but did not depend on the agonist (aspartate; Asp) concentration. Blockade by AM and A-7, but not Mg2+, was weakly use dependent. 'Hooked' tail currents were observed after coapplication of Asp and Mg2+, AM or A-7. The hooked tail current kinetics, amplitude and carried charge indicated that Mg2+, AM and A-7 did not prevent closure and desensitization of NMDA channels nor agonist dissociation. Tail currents following Asp application in the absence and continuous presence of Mg2+, AM or A-7 had similar kinetics. Application of multiple stationary and kinetic criteria to the Mg2+, AM and A-7 blockade led us to conclude that their effects on NMDA channels can be described in terms of a 'trapping' model, which is fully symmetrical with respect to the blocking transition. In general, the apparent blocking/recovery kinetics predicted by the fully symmetrical trapping model differ significantly from the microscopic kinetics and depend on the rate of binding and unbinding of the blocker, the NMDA channel open probability and the rate of solution exchange.