TRAPPING OF ORGANIC BLOCKERS BY CLOSING OF VOLTAGE-DEPENDENT K- EVIDENCE FOR A TRAP DOOR MECHANISM OF ACTIVATION GATING( CHANNELS )

Small organic molecules, like quaternary ammonium compounds, have long been used to probe both the permeation and gating of voltage-dependen t K+ channels. For most K+ channels, intracellularly applied quaternar y ammonium (OA) compounds such as tetraethylammonium (TEA) and decyltr iethylammonium (C-10) behave primarily as open channel blockers: they can enter the channel only when it is open, and they must dissociate b efore the channel can close. In some cases, it is possible to force th e channel to close with a QA blocker still bound, with the result that the blocker is ''trapped.'' Armstrong (J. Gen. Physiol. 58:413-437) f ound that at very negative voltages, squid axon K+ channels exhibited a slow phase: of recovery from QA blockade consistent with such trappi ng. In our studies on the cloned Shaker channel, we find that wild-typ e channels can trap neither TEA nor C-10, but channels with a point mu tation in S6 can trap either compound very efficiently. The trapping o ccurs with very little change in the energetics of channel gating, sug gesting that in these channels the gate may function as a trap door or hinged lid that occludes access from the intracellular solution to th e blocker site and to the narrow ion-selective pore.