Mallotoxin Is a Novel HumanEther-a-go-go-Related Gene (hERG) Potassium Channel Activator

Abstract

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 or 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 currents with EC 50 values of 0.34 and 0.52 M, respectively. MTX leftward shifted the voltage dependence of hERG channel activation to less depolarized voltages (ϳ24 mV at 2.5 M). 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 prerecorded cardiac action potentials, 2.5 M MTX increased the total potassium ions passed through hERG channels by ϳ5-fold. In conclusion, MTX activates hERG channels through distinct mechanisms and with significantly higher potency than previously reported hERG channel activators.The human ether-a-go-go-related gene (hERG) (Warmke and Ganetzky, 1994) encodes rapidly activating delayed rectifier potassium channels that conduct the cardiac I Kr (Sanguinetti et al., 1995;Trudeau et al., 1995). Although existing in many different cell types (Warmke and Ganetzky, 1994;Farrelly et al., 2003;Sarzani et al., 2006), hERG channels are highly expressed in cardiac myocytes where they function to restore resting membrane potential after action potential generation (for a recent review, see Sanguinetti and TristaniFirouzi, 2006).Many drugs with varying structures and therapeutic targets have been found to block hERG channels, which, in turn, prolong the QT interval and cause long QT syndrome (De Ponti et al., 2000, 2002 We report for the first time that mallotoxin (MTX), a natural occurring substance, is a potent and unique hERG channel activator. MTX, extracted from a tree named Mallotus phillippinensis, was originally described as an inhibitor for protein kinase C (PKC), Ca 2ϩ /calmodulin-dependent protein kinase II and III, and elongation factor-2 kinase (Gschwendt et al., 1994a,b). Recently, MTX has been shown to potently leftward shift the conductance-voltage relationship of the large conductance voltage and Ca 2ϩ -activated K ϩ channel (Zakharov et al., 2005). When we tested MTX on hERG channels, we found that MTX increased both step and tail hERG current by leftward shifting the voltage dependence of hERG activation and slowing channel deactivation. These actions distinguish MTX as a novel naturally occurring hERG channel activator. Materials and MethodsCell ...

K+ Channel Modulators for the Treatment of Neurological Disorders and Autoimmune Diseases

“…147 However, mallotoxin is not specific for K Ca 1.1 and also activates K V 11.1 (hERG) channels. 148 An endogenous compound that activates K Ca 1.1 channels by binding to an extracellular site on the 1-subunit is the female hormone 17 -estradiol (EC 50 2.4 µM). 149 This K Ca 1.1 activation has been suggested to be at least partially responsible for the direct vasorelexant effect of estrogens.…”

Structure, Function, and Modification of the Voltage Sensor in Voltage-Gated Ion Channels

“…Molecules activating hERG have also been found [172][173][174][175][176]. Furthermore, auxiliary subunits can also work as binding sites for some channel activators [177].…”

Activation of human ether-a-go-go related gene (hERG) potassium channels by small molecules

“…Most of the existing activators originated from combinatorial chemistry libraries, including RPR260243 [22][23][24] , PD-118057 [25] , PD-307243 [26] , NS1643 [27] , NS3623 [28] , A-935142 [29] , ICA-105574 [30] , and KB130015 [31] . Addi-www.nature.com/aps Zhou PZ et al Acta Pharmacologica Sinica npg tionally, a natural product, mallotoxin, has also been shown to activate hERG [32] . Below, we review the literature on individual compounds.…”

“…Based on its similarity to amiodarone, KB130015 presumably binds to the hERG pore from the cytosolic side and functionally competes with blockade by amiodarone and other canonical inhibitors at this site [31] . [32] . The potency of MTX is at least ten fold higher than previously reported hERG activators, including PD-118057, NS1643, and RPR260243.…”

“…It mainly affects channel activation (left-shifting the activation curve by +24 mV at 2.5 μmol/L MTX) and deactivation without modulating inactivation. Using pre-recorded cardiac action potentials, 2.5 μmol/L MTX increases the total number of potassium ions passed through hERG channels by ~5-fold [32] .…”