Charged drug interactions at the inner mouth of K+ channels:: Information gained from gating current studies

Potassium channels are integral membrane proteins which have a central role in the control of the cell environment and excitability. Gating in voltage-dependent K+ channels (Kv channels) is transduced by well-defined structural motifs that move out of the membrane in response to an applied electric field. Information about channel transitions that occur prior to opening is provided by gating currents, which reflect movement of these charged structures as transitions between kinetic closed states. Current models of gating depend heavily on information obtained from such studies. By studying modulation of the gating properties of K+ channels by cations and with drugs, a more complete interpretation of the state-dependence of drug and ion interactions with the channel can be made. In this way we can uncover the detailed mechanisms of action of K+ channel blockers such as tetraethylammonium ions and 4-aminopyridine, and antiarrhythmic agents such as nifedipine and quinidine.