Liin Sara I, Silverå Ejneby Malin, Barro-Soria Rene, Skarsfeldt Mark Alexander, Larsson Johan E, Starck Härlin Frida, Parkkari Teija, Bentzen Bo Hjorth, Schmitt Nicole, Larsson H Peter, Elinder Fredrik
Department of Physiology and Biophysics, University of Miami, Miami, FL 33136; Department of Clinical and Experimental Medicine, Linköping University, SE-581 85 Linköping, Sweden;
Department of Clinical and Experimental Medicine, Linköping University, SE-581 85 Linköping, Sweden;
Proc Natl Acad Sci U S A. 2015 May 5;112(18):5714-9. doi: 10.1073/pnas.1503488112. Epub 2015 Apr 21.
Polyunsaturated fatty acids (PUFAs) affect cardiac excitability. Kv7.1 and the β-subunit KCNE1 form the cardiac IKs channel that is central for cardiac repolarization. In this study, we explore the prospects of PUFAs as IKs channel modulators. We report that PUFAs open Kv7.1 via an electrostatic mechanism. Both the polyunsaturated acyl tail and the negatively charged carboxyl head group are required for PUFAs to open Kv7.1. We further show that KCNE1 coexpression abolishes the PUFA effect on Kv7.1 by promoting PUFA protonation. PUFA analogs with a decreased pKa value, to preserve their negative charge at neutral pH, restore the sensitivity to open IKs channels. PUFA analogs with a positively charged head group inhibit IKs channels. These different PUFA analogs could be developed into drugs to treat cardiac arrhythmias. In support of this possibility, we show that PUFA analogs act antiarrhythmically in embryonic rat cardiomyocytes and in isolated perfused hearts from guinea pig.
多不饱和脂肪酸（PUFAs）会影响心脏兴奋性。Kv7.1和β亚基KCNE1形成心脏IKs通道，该通道对心脏复极化至关重要。在本研究中，我们探讨了多不饱和脂肪酸作为IKs通道调节剂的前景。我们报告多不饱和脂肪酸通过静电机制打开Kv7.1。多不饱和脂肪酸打开Kv7.1既需要多不饱和酰基尾，也需要带负电荷的羧基头部基团。我们进一步表明，KCNE1共表达通过促进多不饱和脂肪酸质子化消除了多不饱和脂肪酸对Kv7.1的作用。具有降低的pKa值以在中性pH下保持其负电荷的多不饱和脂肪酸类似物恢复了打开IKs通道的敏感性。具有带正电荷头部基团的多不饱和脂肪酸类似物会抑制IKs通道。这些不同的多不饱和脂肪酸类似物可被开发成治疗心律失常的药物。为支持这种可能性，我们表明多不饱和脂肪酸类似物在胚胎大鼠心肌细胞和豚鼠离体灌注心脏中具有抗心律失常作用。
