Session Speaker

The voltage sensor in IKs channels may be an ideal drug target for cardiac arrhythmias
Jianmin Cui
USA

The IKs channel is found in cardiac muscle cells and in some neurons. The major function of the IKs channel is to terminate cardiac action potentials and thus maintain a proper heart rhythm. Mutations in the IKs channel protein that reduce its expression or alter its function have been associated with atrial fibrillation and the long Q-T syndrome (LQT), which causes syncope and sudden death in patents. The IKs channel is comprised of two kinds of subunits, KCNQ1 and KCNE1. In the study of an LQT-associated mutation in KCNQ1, we found that the mutation disrupts electrostatic interactions between the S2 and the S4 transmembrane segments in the voltage sensor domain of the channel. These electrostatic interactions determine voltage dependent activation of the channel and are crucial for IKs channel function. We found that extracellular reagents can modify the electrostatic interactions in the IKs channel to either enhance or reduce channel function. Such modulations are highly specific to the IKs channels because in the absence of the KCNE1 subunit, the channels formed by the KCNQ1 subunits were not sensitive. Our findings reveal that the interactions between S2 and S4 in the IKs channel are an ideal drug target with the following advantages. A) The modification of the interaction may either increase or decrease IKs channel function. Therefore, different drugs may be developed to up- or down-regulate the channel activity to affect heart rhythm. B) Extracellular drugs may modify these interactions. Thus, during drug development, there is no need to consider the difficulties normally associated with drug entry into the cell. C) These interactions can be modified only when KCNE1 is part of the channel complex. This specificity for the IKs channel ensures that the drugs will not affect other potassium channels that are homologous to KCNQ1 but do not associate with KCNE1. Therefore, the side effects of these drugs are minimal.