Physical Determinants of Strong Voltage Dependence of K+ Channel Block

Abstract

Many pharmacological agents, as well as some endogenous biological molecules, act by blocking ion channels in a strongly voltage-dependent manner. In retrospect, the first and most dramatic example of such action is the “anomalous” voltage dependence of inwardly rectifying K+ (Kir) conductance discovered by Bernard Katz six decades ago. He observed that, contrary to the classic voltage-gated K+ conductance, the Kir conductance tends to zero with membrane depolarization but increases with hyperpolarization. In intact cells and within physiological voltage ranges, certain Kir channels are as steeply voltage dependent as Kv channels yet, unlike Kv channels, they have no inherent voltage sensors: the observed voltage sensitivity instead reflects voltage-dependent block of their ion pore by intracellular cations such as the polyamine spermine. Our group has proposed that the high valence associated with block of strong rectifiers primarily reflects the movement, not of tetravalent spermine itself, but of five K+ ions displaced by spermine across the steep electric field in the narrow K+ selectivity filter. We will present experimental evidence for key requirements of this blocker-K+ displacement model, and will discuss the essential features that render a pore-blocking process strongly voltage dependent.