Quinidine enhances and suppresses Kv1.2 from outside and inside the cell, respectively

We studied the effects of quinidine on two K channel clones expressed in Xenopus oocytes, Kv1.2 and Kv1.4. Quinidine had an agonist (enhancement) and a blocker (suppression) action on Kv1.2, whereas only the blocker action was seen with Kv1.4. For both, the blocker action was exerted from the intracellular side of the membrane due to quinidine binding in its protonated form to a site in the membrane electrical field. The agonist action on Kv1.2 was exerted from the extracellular side of the membrane. A quaternary analog of quinidine, Q+1C, that had a low membrane permeability allowed the agonist action to be separated from the blocker action. Experiments with Q+1C showed that the agonist action was caused by a parallel shift of the voltage dependence of Kv1.2 activation in the negative direction. There was no increase in channel conductance when channel activation reached a plateau. Q+1C had little or no effect on the rate of Kv1.2 activation, but significantly slowed Kv1.2 deactivation at voltages as negative as - 160 mV. These changes in channel gating could be largely reproduced by a simple kinetic model, assuming that the agonist action was caused by a decrease in the rate constants for transitions from the activated to the rested states. In oocytes coexpressing Kv1.2 and Kv1.4 at approximately a 1:1 ratio, the response to Q+1C was similar to that of oocytes expressing Kv1.2 alone, suggesting that heteromultimer channels of Kv1.2 and Kv1.4 subunits could respond to the agonist action of quinidine.