Intrinsic Versus Extrinsic Voltage Sensitivity of Blocker Interaction with an Ion Channel Pore

Many physiological and pharmacological agents act by occluding the conduction pore of ion channels. A hallmark of charged blockers is that their apparent affinity for the pore usually varies significantly with membrane voltage. Two models have been proposed to explain voltage dependence of channel block. One model - prevalent during the past three decades - assumes that the charged blocker itself directly senses the transmembrane electric field, i.e., that blocker binding is intrinsically voltage dependent. In the alternative model, the blocker does not directly interact with the electric field; instead, blocker binding acquires apparent voltage dependence solely through the concurrent movement of permeant ions across the field. Although less frequently invoked, this latter model may better explain voltage dependence of channel block by large organic compounds that are too bulky to fit into the narrow part of the pore where the electric field is steep. To date no systematic investigation has been carried out to distinguish between these voltage-dependent mechanisms of channel block. When the voltage dependence of block by organic compounds is believed to be extrinsic, it has never been demonstrated that the block can be rendered voltage independent - the most fundamental characteristic of the extrinsic mechanism. In the present study we find that a retinal cyclic nucleotide-gated (CNG) channel can be blocked via either mechanism, depending on the nature of the blocker. With this channel as a model, we systematically examine both intrinsic and extrinsic types of voltage dependence of channel block, and illustrate their electrophysiological hallmarks and analytical characteristics.