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Mechanisms Underlying the Dual Effect of Polyunsaturated Fatty Acid Analogs on Kv7.1

Sara I Liin¹, Samira Yazdi¹, Rosamary Ramentol²

¹Department of Clinical and Experimental Medicine, Linköping University, 581 85 Linköping, Sweden.

|September 13, 2018

Abstract:

Polyunsaturated fatty acid (PUFA) analogs represent a new class of potential anti-arrhythmic KV7.1 and KV7.1+KCNE1 channel activators. In this study, we describe dual independent activating effects of negatively charged PUFA analogs on KV7.1 and KV7.1+KCNE1 that are dependent on discrete channel motifs. PUFA analogs are critically dependent on K326 in S6 of KV7.1 to increase the maximum conductance and critically dependent on specific S4 arginines in KV7.1 to shift the voltage dependence of channel opening toward negative voltages. Our findings provide insights into how KV7.1+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 KV7.1 channels.

Keywords:

I(Ks) activator I(Ks) channel KCNE1 KCNQ1 Xenopus oocyte cardiac arrhythmia polyunsaturated fatty acid two-electrode voltage clamp

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