Molecular basis of permeation in voltage-gated ion channels.

J on channels are pore-forming macromolecules that provide a passive conduit for ion transfer across membranes. Although simple ionophores such as gramicidin and nystatin' fall within this legalistic definition, the ion channels of eukaryotic cells are integral membrane proteins, many of which have now been isolated biochemically, reconstituted, cloned, and expressed. These fascinating proteins play a particularly prominent role in the function of the cardiovascular system by conferring excitability in an exquisitely tissuespecific manner and by mediating a number of key steps in signal transduction. The ion channels in a nodal cell enable it to pace, whereas those in a myocyte enable it to contract. In addition to mediating ionic fluxes across cell membranes, ion channels are the primary receptors for a variety of clinically important drugs including antiarrhythmic agents and calcium channel antagonists.' Therefore, it is of considerable interest to cardiovascular biologists to consider how ion channels work. Two distinct sets of properties characterize each type of ion channel: those that determine whether the channel is open or closed, collectively known as the "gating" properties, and those that define just how the channel moves ions when it is open, known as the "permeation" properties. The structure-function correlation of voltage-gated ion channels is the subject of several general reviews. The present Mini Review focuses specifically on the mechanism of permeation in ion channels, with particular emphasis on the structural domains that form the pore, determine selectivity, and interact with poreblocking molecules.