![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
|
|
|
|
|
||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Received for publication July 11, 2006.
Revised August 15, 2006.
Accepted for publication August 21, 2006.
Human ether-a-go-go-related gene (hERG) encodes a rapidly activating delayed rectifier potassium channel that plays important roles in cardiac action potential repolarization. Although many drugs and compounds block hERG channels, activators of the channel have only recently been described. Three structurally diverse synthetic compounds have been reported to activate hERG channels by altering deactivation, inactivation, or by unidentified mechanisms. Here, we describe a novel, naturally occurring hERG channel activator, Mallotoxin (MTX). The effects of MTX on hERG channels were investigated using the patch-clamp technique. MTX increased both step and tail hERG current with an EC50 of 0.34 and 0.52 µM, respectively. MTX leftward shifted the voltage-dependence of hERG channel activation to less depolarized voltages (~24 mV at 2.5 µM). In addition, MTX increased hERG deactivation time constants. MTX did not change the half-maximal inactivation voltage of the hERG channel, but it reduced the slope of the voltage-dependent inactivation curve. All of these factors contribute to the enhanced activity of hERG channels. During a voltage-clamp protocol using pre-recorded cardiac action potential, 2.5 µM MTX increased the total potassium ions passed through hERG channels by ~5-fold. In conclusion, MTX activates hERG channels through distinct mechanisms and with significantly higher potency than previously reported hERG channel activators.
Key words:
action potential, activation, channel modulation, deactivation, ion channel, toxin
This article has been cited by other articles:
|
|
 |
|
  H. Zeng, E. Gordon, Z. Lin, I. M. Lozinskaya, R. N. Willette, and X. Xu 1-[1-Hexyl-6-(methyloxy)-1H-indazol-3-yl]-2-methyl-1-propanone, a Potent and Highly Selective Small Molecule Blocker of the Large-Conductance Voltage-Gated and Calcium-Dependent K+ Channel J. Pharmacol. Exp. Ther., October 1, 2008; 327(1): 168 - 177. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. N. Willette, W. Bao, S. Nerurkar, T.-l. Yue, C. P. Doe, G. Stankus, G. H. Turner, H. Ju, H. Thomas, C. E. Fishman, et al. Systemic Activation of the Transient Receptor Potential Vanilloid Subtype 4 Channel Causes Endothelial Failure and Circulatory Collapse: Part 2 J. Pharmacol. Exp. Ther., August 1, 2008; 326(2): 443 - 452. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. G. Diness, Y.-H. Yeh, X. Y. Qi, D. Chartier, Y. Tsuji, R. S. Hansen, S.-P. Olesen, M. Grunnet, and S. Nattel Antiarrhythmic properties of a rapid delayed-rectifier current activator in rabbit models of acquired long QT syndrome Cardiovasc Res, July 1, 2008; 79(1): 61 - 69. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Gordon, I. M. Lozinskaya, Z. Lin, S. F. Semus, F. E. Blaney, R. N. Willette, and X. Xu 2-[2-(3,4-Dichloro-phenyl)-2,3-dihydro-1H-isoindol-5-ylamino]-nicotinic Acid (PD-307243) Causes Instantaneous Current through Human Ether-a-go-go-Related Gene Potassium Channels Mol. Pharmacol., March 1, 2008; 73(3): 639 - 651. [Abstract] [Full Text] [PDF]
|
|
 |
 |
 |
|
 |
 |
 |
