Key result
The voltage dependence of external TEA block of Shaker K+ channels disappears when K+ ions are replaced by Rb+, suggesting the TEA binding site is outside the membrane electric field.
The external TEA binding site is not within the membrane electric field, and the voltage dependence of TEA block in K+ solutions arises through coupling with the movement of K+ ions.
Should not yet guide clinical K+ channel blocker use; extends mechanistic models of TEA block in voltage-gated channels.
Recent molecular dynamic simulations and electrostatic calculations suggested that the external TEA binding site in K+ channels is outside the membrane electric field. However, it has been known for some time that external TEA block of Shaker K+ channels is voltage dependent. To reconcile these two results, we reexamined the voltage dependence of block of Shaker K+ channels by external TEA. We found that the voltage dependence of TEA block all but disappeared in solutions in which K+ ions were replaced by Rb+. These and other results with various concentrations of internal K+ and Rb+ ions suggest that the external TEA binding site is not within the membrane electric field and that the voltage dependence of TEA block in K+ solutions arises through a coupling with the movement of K+ ions through part of the membrane electric field. Our results suggest that external TEA block is coupled to two opposing voltage-dependent movements of K+ ions in the pore: (a) an inward shift of the average position of ions in the selectivity filter equivalent to a single ion moving approximately 37% into the pore from the external surface; and (b) a movement of internal K+ ions into a vestibule binding site located approximately 13% into the membrane electric field measured from the internal surface. The minimal voltage dependence of external TEA block in Rb+ solutions results from a minimal occupancy of the vestibule site by Rb+ ions and because the energy profile of the selectivity filter favors a more inward distribution of Rb+ occupancy.
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Thompson et al. (2003) studied this question. External TEA block in K+ solutions vs. Rb+ solutions was evaluated on Voltage dependence of TEA block. The voltage dependence of external TEA block of Shaker K+ channels disappears when K+ ions are replaced by Rb+, suggesting the TEA binding site is outside the membrane electric field.
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