Common binding site for externally and internally applied AMPA receptor channel blockers.

Adamantane derivative IEM-1676 (Ad-N(+)H(2)-(CH(2))(5)-N(+)Me(3)) causes open-channel block of Ca(2+)-permeable AMPA receptors when applied externally, but internal application results in both closed- and open-channel block. The relationships between blocking action of externally and internally applied IEM-1676 were studied using patch clamp technique. Extracellular action of IEM-1676 was decreased by its intracellular application, thus suggesting that the binding sites of the externally and internally applied drug coincide or at least overlap significantly. We demonstrated that internal closed-channel block is voltage-dependent and occurs at the region where the externally applied drug is trapped. We conclude that the selectivity filter of the closed AMPA receptor channel is not occluded and remains permeable for organic cations.