Papaverine, a vasodilator, blocks the pore of the HERG channel at submicromolar concentration.
Papaverine, a vasodilator used as a therapeutic agent for a range of diseases, has been reported to increase the risk of occasional serious ventricular arrhythmias. To examine the mechanism for this effect, we herein tested the effects of papaverine on human ether-a-go-go (HERG) K channels expressed in HEK293 cells and Xenopus oocytes. Our results revealed that papaverine dose-dependently decreased the tail currents of HERG channel expressed in HEK293 cells with the IC50 and the Hill coefficient of 0.58 microM and 0.58, respectively, at +20 mV and 36 degrees C. The IC50 for the papaverine-induced blockade of HERG current in Xenopus oocytes was found to decrease progressively relative to depolarization (38.8, 30.0, and 24.8 microM at -10, +20, and +40 mV, respectively). The papaverine-induced blockade of HERG current was time-dependent; the fractional current was 0.92 +/- 0.03 of the control at the beginning of the pulse, but it declined to 0.18 +/- 0.06 after 6 seconds at a test potential of 0 mV. These results collectively indicate that papaverine blocks HERG channel in a concentration-, voltage-, and time-dependent manner. Two S6 domain mutations, Y652A and F656A, partially attenuated (Y652A) or abolished (F656A) the hERG current blockade, suggesting that papaverine blocks HERG channel at the pore of the channel. This was consistent with the computational simulation that showed papaverine interacts with Tyr652 and Phe656. Therefore, ventricular arrhythmias induced by papaverine could be resulted from the blockage of the HERG channel at the cardiac myocytes.
Kim
Young Jin
YJ
Department of Physiology and Research Institute for Biomacromolecules, University of Ulsan College of Medicine, Seoul, Korea.
Hong
Hee Kyung
HK
Lee
Hui Sun
HS
Moh
Sang Hyun
SH
Park
Jong Cook
JC
Jo
Su Hyun
SH
Choe
Han
H
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced* / Q000378:metabolism; D002460:Cell Line; D003198:Computer Simulation; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008564:Membrane Potentials; D008958:Models, Molecular; D015394:Molecular Structure; D009154:Mutation; D010208:Papaverine / Q000737:chemistry / Q000633:toxicity*; D026902:Potassium Channel Blockers / Q000737:chemistry / Q000633:toxicity*; D011487:Protein Conformation; D013997:Time Factors; D014162:Transfection; D014665:Vasodilator Agents / Q000737:chemistry / Q000633:toxicity*; D014982:Xenopus laevis
D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D026902:Potassium Channel Blockers; D014665:Vasodilator Agents; D010208:Papaverine