DIVERSE EFFECTS OF QUINIDINE ON K-CHANNELS REVEALED BY STUDIES ON K-CHANNEL CLONES

We studied the effects of quinidine and its quaternary analogue on thr ee cardiac K channel clones (Kv1.4, Kv1.2, and IsK) expressed in Xenop us oocytes. Three modes of action of quinidine were identified. First, for Kv1.4 and Kv1.2, quinidine was a fast ''open'' channel blocker fr om the cytoplasmic side of the membrane. Block was enhanced by membran e depolarization in the voltage range where channel activation reached a plateau, suggesting that quinidine blocked these channels in its pr otonated form by binding to a site in the membrane electrical field. T he binding site had an equivalent electrical distance of 0.2-0.3 from the intacellular surface. Second, quinidine also suppressed IsK from t he intracellular side of the membrane. However, in contrast to Kv1.4 a nd Kv1.2, block of IsK by quinidine was enhanced by membrane hyperpola rization but reduced by membrane depolarization, suggesting that quini dine may preferentially bind to IsK channels in the closed state and p revent them from opening. Finally, quinidine had an ''agonist'' effect on Kv1.2 but not on Kv1.4 or IsK. Quinidine caused a negative shift i n the voltage-dependence of Kv1.2 activation, leading to an increase i n its amplitude at negative voltages. Quinidine exerts its agonist act ion from the extracellular side of the cell membrane. We conclude that quinidine has diverse effects on different K channels, and K channel clones may provide a useful model system to explore the structural bas is for different components of quinidine's actions.