Abstract
Polyunsaturated fatty acid (PUFA) analogs are potentially anti-arrhythmic compounds, and understanding their functional mechanisms can aid in rational drug design. Liin et al. find that negatively charged PUFA analogs activate the cardiac potassium channel K
V
7.1 by dual independent mechanisms, demonstrating augmentation of channel activity through electrostatic interactions with both the pore and voltage-sensing domains of K
V
7.1.
Polyunsaturated fatty acid (PUFA) analogs represent a new class of potential anti-arrhythmic K
V
7.1 and K
V
7.1+KCNE1 channel activators. In this study, we describe dual independent activating effects of negatively charged PUFA analogs on K
V
7.1 and K
V
7.1+KCNE1 that are dependent on discrete channel motifs. PUFA analogs are critically dependent on K326 in S6 of K
V
7.1 to increase the maximum conductance and critically dependent on specific S4 arginines in K
V
7.1 to shift the voltage dependence of channel opening toward negative voltages. Our findings provide insights into how K
V
7.1+KCNE1 activators may interact electrostatically both with the pore domain and the voltage-sensing domain to augment channel activity. We believe that the molecular understanding of how PUFA analogs induce dual independent activating effects is an important step toward the development of effective anti-arrhythmic drugs that target K
V
7.1 channels.
