The amiodarone derivative KB130015 activates hERG1 potassium channels via a novel mechanism.

European Journal of Pharmacology
Guido GessnerStefan H Heinemann

Abstract

Human ether à go-go related gene (hERG1) potassium channels underlie the repolarizing I(Kr) current in the heart. Since they are targets of various drugs with cardiac side effects we tested whether the amiodarone derivative 2-methyl-3-(3,5-diiodo-4-carboxymethoxybenzyl)benzofuran (KB130015) blocks hERG1 channels like its parent compound. Using patch-clamp and two-electrode voltage-clamp techniques we found that KB130015 blocks native and recombinant hERG1 channels at high voltages, but it activates them at low voltages. The activating effect has an apparent EC(50) value of 12microM and is brought about by an about 4-fold acceleration of activation kinetics and a shift in voltage-dependent activation by -16mV. Channel activation was not use-dependent and was independent of inactivation gating. KB130015 presumably binds to the hERG1 pore from the cytosolic side and functionally competes with hERG1 block by amiodarone, E4031 (N-[4-[[1-[2-(6-methyl-2-pyridinyl)ethyl]-4-piperidinyl] carbonyl] phenyl] methanesulfonamide dihydrochloride), and sertindole. Vice versa, amiodarone attenuates hERG1 activation by KB130015. Based on synergic channel activation by mallotoxin and KB130015 we conclude that the hERG1 pore contains at least two s...Continue Reading

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Citations

May 31, 2011·Acta Pharmacologica Sinica·Ping-zheng ZhouZhao-bing Gao
Nov 13, 2015·Expert Review of Cardiovascular Therapy·A BossuM A Vos
Apr 12, 2014·Current Opinion in Pharmacology·Michael C Sanguinetti
Jul 21, 2010·The Journal of Physiology·Matthew PerryJohn Mitcheson
Jun 5, 2016·Cardiac Electrophysiology Clinics·Wei Wu, Michael C Sanguinetti
Nov 4, 2016·Physiological Reviews·M S BohnenR S Kass
Jan 25, 2019·The Journal of General Physiology·Kazuharu FurutaniYoshihisa Kurachi
Sep 20, 2012·Physiological Reviews·Jamie I VandenbergAdam P Hill
Jun 27, 2019·Antimicrobial Agents and Chemotherapy·Daniel FischerSascha Brunke
Dec 3, 2014·Chemical & Pharmaceutical Bulletin·Ghaneya Sayed HassanGehad Abdel Raheem Abdel Jaleel

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