A mechanistic understanding of how KCNE1 tunes KCNQ1 channel pharmacology

The IKs potassium channel that is essential for cardiac repolarization is formed by KCNQ1 and KCNE1 subunits. Promising activators of KCNQ1 need to affect KCNQ1-KCNE1 to be used as therapeutics to prevent cardiac arrythmia. Unfortunately, KCNE1 dramatically impairs several KCNQ1 activators. How KCNE1 changes the sensitivity of KCNQ1 to various compounds is unknown, limiting rational design of IKs channel activators. KCNE1 has been proposed to induce a conformational change in the S5-P loop of KCNQ1. Here, we examine the effects of K285Q in the S5-P loop on the sensitivity of KCNQ1 and IKs to polyunsaturated fatty acid (PUFA) analogs. We find that K285Q causes PUFA analogs to have different effects in KCNQ1 versus IKs, suggesting that the S5-P loop moves between two different PUFA sites when KCNE1 associates with KCNQ1. This will allow for a mechanistic framework to design IKs channel activators that circumvent KCNE1-induced impairment of drug binding.