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CELLULAR AND MOLECULAR

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

Cardiovascular and Urogenital Center of Excellence in Drug Discovery, GlaxoSmithKline, King of Prussia, Pennsylvania

Received July 10, 2006; accepted August 21, 2006.

	Abstract

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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 EC₅₀ values 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 prerecorded cardiac action potentials, 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.

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). However, hERG channel openers have been described only recently. RPR260243 (Kang et al., 2005), PD-118057 (Zhou et al., 2005), and NS1643 (Casis et al., 2006; Hansen et al., 2006) are distinct chemical entities that activate hERG channels through a variety mechanisms, i.e., by slowing channel deactivation, by reducing channel inactivation, or by unidentified mechanisms. To date, no naturally occurring hERG channel activators have been identified.

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), Ca²⁺/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 Ca²⁺-activated K⁺ 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 Methods

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Cell Culture. Chinese hamster ovary (CHO) cells were stably transfected to express hERG channels (Biocat ID: 97761; GlaxoSmithKline, King of Prussia, PA) and used for patch-clamp recording. The reason we chose CHO cells to stably express hERG channels is that CHO cells have little endogenous, voltage-dependent potassium channels and therefore are widely used to express voltagegated potassium channels (Zeng et al., 2005). CHO cells were maintained at 37°C with 5% CO₂ in six-well culture dishes with Iscoves Dulbecco's modified Eagle's medium F-12 nutrient mixture, supplemented with 10% fetal bovine serum, 100 U/ml penicillin and streptomycin, and 0.5 mg/ml geneticin (Invitrogen, Carlsbad, CA).

Patch Clamp. Whole-cell and inside-out patch currents were recorded from CHO cells stably expressing hERG channels with an Axopatch 200B amplifier and Digidata 1322A digitizer (Molecular Devices, Union City, CA). Glass electrodes (2–4 M resistance) were pulled from thin-wall glass (WPI, Sarasota, FL) using a P-97 horizontal puller (Sutter, Novato, CA) and fire polished with a MF-830 microforge (Narishige, Long Island, NY). In whole-cell recording, the bath solution contained 140 mM NaCl, 4 mM KCl, 1 mM MgCl₂, 2 mM CaCl₂, 10 mM glucose, and 10 mM HEPES, pH 7.4 with NaOH. The pipette solution contained 119 mM potassium gluconate, 15 mM KCl, 5 mM EGTA, 5 mM K₂ATP, 3.2 mM MgCl₂, 0.01 mM phosphatidylinositol bisphosphate, and 5 mM HEPES, pH 7.2 with KOH. In inside-out patch recording, both bath and pipette solutions contained 140 mM KCl, 1 mM MgCl₂, 2 mM CaCl₂, and 5 mM HEPES, pH 7.2 with KOH. Currents were elicited by different voltage protocols (described in the text and figure legends) and acquired with pCLAMP 8 software (Molecular Devices) at room temperature.

Chemicals. MTX (Sigma-Aldrich, St. Louis, MO), also called rottlerin (see inset of Fig. 1B for structure), and dofetilide (APIN Chemicals LTD, Abingdon, UK) were made as 10 mM dimethyl sulfoxide stock solutions and diluted in external buffer solutions to the desired concentrations. The highest dimethyl sulfoxide concentration in solution was 0.1%. The effects of MTX on hERG channels were measured at the steady state. Each cell was exposed to a single concentration of MTX; in addition, two cells were tested at both 0.1 and 10 µM.

View larger version (19K): [in this window] [in a new window]   Fig. 1. MTX increased both step and tail hERG currents. A, whole-cell currents are elicited by a voltage-clamp protocol (inset) before and after application of 2.5 µM MTX and 2.5 µM MTX + 100 nM dofetilide. B, time course of the step () and peak tail current amplitudes (). The application of MTX (inset) and dofetilide is indicated by arrows. C, inside-out macro-patch currents are elicited by a voltage-clamp protocol (inset) before, after application of 2.5 µM MTX, and after wash.

	Results

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hERG current in CHO cells was induced by a 2-s depolarizing step to +20 mV from a holding potential of –80 mV, followed by a 2-s repolarizing step to –50 mV to measure tail current and repeated at 10-s interval (Fig. 1A, inset). The effects of 2.5 µM MTX on hERG current and its time course are illustrated in Fig. 1. MTX increased the amplitude of both step and tail currents (Fig. 1A). The effects of MTX developed gradually and reached steady state in 6 to 7 min (Fig. 1B). The MTX-activated current was completely blocked by 100 nM dofetilide, a potent hERG channel blocker (Snyders and Chaudhary, 1996; Kamiya et al., 2006). In the inside-out patch setting, similar results were observed when MTX was applied to the cytoplasmic side of the channel, and the effect was washable (Fig. 1C). Peak tail current amplitude increased by 140 ± 40% (n = 4).

We then used different voltage-clamp protocols to study the effects of MTX on hERG channels in more detail. hERG currents were elicited by 2-s depolarizing steps to different voltages (from –70 to +60 mV in 10-mV increments) from a holding potential of –80 mV, followed by a 2-s hyperpolarizing step to –50 mV to measure tail currents (Fig. 2A, inset). MTX increased step and tail current amplitudes in a broad range of membrane potentials (Fig. 2B), and dofetilide (100 nM) blocked hERG currents activated by MTX (Fig. 2C).

View larger version (22K): [in this window] [in a new window]   Fig. 2. MTX activated hERG channels at various membrane potentials. Whole-cell currents were induced by a voltage-clamp protocol (inset) before (A) and after the application of 2.5 µM MTX (B) and 2.5 µM MTX + 100 nM dofetilide (C).

View larger version (21K): [in this window] [in a new window]   Fig. 3. MTX activated hERG channels in a concentration-dependent manner. Normalized step (A) and peak tail current-voltage relationships (B) were generated as described in the text in the absence and presence of 0.1, 0.5, 2.5, and 10 µM MTX. Normalized peak tail current-voltage relationships were fitted with the Boltzmann equation to obtain V1/2 and slope factor (k): I/Imax = 1/(1 + exp[(V1/2 – Vt)/k]). The dose response of MTX (C) was measured at the 0 mV step () and the following peak tail currents (). Current amplitudes were normalized to the control before MTX application and plotted against MTX concentrations. The resulting curves were fitted with the logistic equation to obtain EC50 values.

For simplicity, we used the step and peak tail currents after the 0 mV depolarization step to determine the concentration-response curves of MTX. EC₅₀ values were 0.34 µM for the step and 0.52 µM for the tail currents (Fig. 3C).

We then studied whether the voltage-dependent inactivation of hERG channels was affected by MTX using a voltage-clamp protocol described by Zou et al. (1998). Currents were elicited by a 1-s depolarizing step pulse to +20 mV from a holding potential of –80 mV, followed by a 10-ms hyperpolarizing step to different voltages (from –150 to 20 mV in 10-mV increments), and then by a 1-s depolarizing step back to +20 mV (Fig. 4, inset). The current amplitude at +20 mV after the 10-ms hyperpolarizing steps to different voltages was normalized by the maximal amplitude after the –150 mV step to obtain the voltage-dependent inactivation curve. The V_1/2 in controls was –57.0 ± 0.4 mV (8) and the slope factor was 20.1 ± 0.4 mV (8). In the presence of 2.5 µM MTX, the V_1/2 and the slope factor were –55.5 ± 0.4 mV (8) and 25.4 ± 0.3 mV (8), respectively. The slope factors were significantly different (P < 0.05), whereas the V_1/2 values were not.

View larger version (18K): [in this window] [in a new window]   Fig. 4. Effect of MTX on voltage-dependent hERG channel inactivation. The voltage-clamp protocol is shown as an inset. Peak tail currents were normalized to the maximal peak tail current and plotted against voltages with () or without 2.5 µM MTX (). The curves were fitted with the Boltzmann function: I/Imax = 1/(1 + exp[(Vt – V1/2)/k]).

We also analyzed the activation and deactivation kinetics of hERG channels in the presence and absence of 2.5 µM MTX. The activation phase of the step currents was well fitted by a single-exponential function. Because of the small amplitudes, traces <0 mV were not used. The activation time constants of hERG channels were decreased significantly (P < 0.05) by 2.5 µM MTX (Fig. 5). Deactivation time constants of hERG channels were derived by fitting the decay phase of tail currents with a double-exponential function (Wang et al., 2003; Kang et al., 2005). In the presence of 2.5 µM MTX, both slow time constants (_s) and fast time constants (_f) were increased significantly compared with the controls (P < 0.05) (Fig. 6). The fraction of the slow component measured by A_s/(A_s + A_f) was also increased significantly by MTX (Fig. 6).

View larger version (18K): [in this window] [in a new window]   Fig. 5. MTX decreased hERG channel activation time constants. In the voltage range from 0 to +50 mV, step currents were fitted with a single-exponential function to obtain the activation time constants with () or without 2.5 µM MTX (). *, P < 0.05.

View larger version (13K): [in this window] [in a new window]   Fig. 6. MTX increased hERG deactivation time constants. In the voltage range from +20 to +50 mV, tail currents were fitted with a double-exponential function to obtain the slow time constants s (A), fast time constant f (B), and the fraction of the slow component (C) with () or without 2.5 µM MTX (). *, P < 0.05.

Finally, we used a prerecorded action potential (Fig. 7A) from rabbit ventricular myocytes as a voltage-clamp stimulus to examine the overall hERG channel responses caused by MTX during an action potential. Current traces before and after MTX application were normalized to the maximal current amplitude of the cell before MTX treatment (Fig. 7B). We integrated the area under positive current traces to calculate the relative change of the total potassium ions conducted by hERG channels. The results demonstrate that 2.5 µM MTX increased the total potassium ions passed through hERG channels by 4.8 ± 0.4-fold (5) during the action potential stimulus. The inward tail current was also significantly increased (Fig. 7B).

View larger version (13K): [in this window] [in a new window]   Fig. 7. MTX increased total potassium ions conducted by hERG channels during an action potential stimulus. Whole-cell currents were excited with a test protocol using a prerecorded action potential trace (A). B, hERG current traces before and after MTX application were normalized to the maximal current amplitude of the cell before MTX treatment. The dotted line indicates zero current.

	Discussion

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We found that MTX, a naturally occurring substance, potently activates hERG channels. It increased both step and tail hERG currents at submicromolar concentrations. It left-ward shifted the voltage dependence of hERG channel activation to less depolarized voltages. In addition, MTX increased hERG deactivation time constants. Therefore, MTX is a novel and potent hERG channel activator with a unique mechanism of action.

MTX is the most potent hERG channel activator reported to date. Compared with the three previously reported hERG channel activators, MTX is at least 10 times more potent than PD-118057 (Zhou et al., 2005), NS1643 (Casis et al., 2006; Hansen et al., 2006), and RPR260243 (Kang et al., 2005). MTX activates hERG channels by mechanisms distinct from those of the other hERG activators. RPR260243 modifies the hERG channel mainly by slowing the deactivation kinetics (Kang et al., 2005), NS1643 reduces hERG channel inactivation (Casis et al., 2006), and PD-118057 changes neither the kinetics nor voltage dependence of hERG channel activation (Zhou et al., 2005). In contrast, MTX activates hERG channels by shifting the voltage dependence of activation to less depolarized voltages. In addition, it also alters the kinetics to make the hERG channel deactivate slower. These actions of MTX on hERG channels resemble the effects of a benzodiazepine L3 on I_ks (KCNQ1 + KCNE1) channels (Salata et al., 1998). The voltage-dependent inactivation of hERG channels is much less sensitive to MTX than its activation, consistent with the idea that the hERG channel has distinct voltage sensors for activation and inactivation (Johnson et al., 1999). The half-maximal inactivation voltage V_1/2 was unaffected by MTX. However, MTX reduced the slope of the voltage-dependent inactivation curve, resulting in reduced hERG inactivation at membrane potentials corresponding to cardiac action potentials. All of these actions contribute to MTX activation of the hERG channel. However, it is unclear whether similar or disparate molecular mechanisms underlie these actions.

The effect of MTX on activation kinetics may be considered secondary to the leftward shift of the voltage dependence of hERG channels, because the activation time constants are not significantly decreased if we adjust for the effect of a negative shift in the channel's voltage dependence of activation caused by MTX (e.g., compare the activation time constant at 10 mV with MTX to the one at 30 mV without MTX).

Because MTX is a PKC inhibitor (Gschwendt et al., 1994b) and hERG channels are regulated by PKC (Barros et al., 1998; Thomas et al., 2003), a question arises as to whether MTX activates hERG channels via PKC inhibition. Our results demonstrated that MTX could activate hERG channels from the cytoplasmic side in an inside-out patch configuration. It is unlikely that secondary messenger systems exist in such a setting. Furthermore, 20 µM MTX has little inhibitory effect on PKC (Davies et al., 2000), whereas 0.5 µM MTX exerts a profound effect on hERG channels. Therefore, it is likely that MTX alters voltage-dependent activation and kinetics of hERG channels by a direct, yet unknown, molecular interaction, but not through kinase inhibition. MTX has been suggested to alter the voltage sensitivity of the large conductance voltage and Ca²⁺-activated K⁺ channel by directly interacting with the voltage sensor or indirectly through modification of the allosteric voltage input (Zakharov et al., 2005). Sphingomyelinase D from spider venom activates the Kv2.1 channel by enzymatically modifying phospholipid (Ramu et al., 2006), which may indicate a direction to further explore the molecular mechanism of MTX activation of hERG channels.

Because MTX affects many aspects of the voltage dependence and kinetics of hERG channels, we used a prerecorded action potential as a voltage stimulus to evaluate the overall increase of potassium ions through hERG channels by MTX. In the presence of 2.5 µM MTX, the increase is approximately 5-fold at room temperature. However, as hERG is very sensitive to temperature (Vandenberg et al., 2006), the effect of MTX on I_Kr during cardiac action potentials could be quite different. Further studies using cardiac myocytes at 37°C and site-directed mutagenesis on hERG channels are required to explore the physiological effects of MTX on cardiac action potentials and the molecular basis of the mechanism(s) of MTX. As a commercially available, potent hERG channel activator, MTX represents a useful tool for the investigation of the physiology of hERG channel physiology and hERG "channelopathies" related to long QT syndrome, short QT syndrome, and cardiac arrhythmias.

	Acknowledgements

 
We thank Dr. Dennis Lee for critical comments on the manuscript.

	Footnotes

 
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

doi:10.1124/jpet.106.110593.

ABBREVIATIONS: hERG, human ether-a-go-go-related gene; I_Kr, rapidly activating delayed rectifier potassium current; RPR260243, (3R,4R)-4-[3-(6-methoxyquinolin-4-yl)-3-oxo-propyl]-1-[3-(2,3,5-trifluoro-phenyl)-prop-2-ynyl]-piperidine-3-carboxylic acid, PD-118057, 2-{4-[2-(3,4-dichloro-phenyl)-ethyl]-phenylamino}-benzoic acid, and NS1643, 1,3-bis-(2-hydroxy-5-trifluoromethyl-phenyl)-urea; MTX, mallotoxin; PKC, protein kinase C; CHO, Chinese hamster ovary; I-V, current-voltage relationship.

Address correspondence to: Dr. Xiaoping Xu, GlaxoSmithKline, 709 Swedeland Rd., UW2511, P.O. Box 1539, King of Prussia, PA 19406. E-mail: Xiaoping.2.Xu{at}gsk.com

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This Article Abstract Full Text (PDF) All Versions of this Article: jpet.106.110593v1 319/2/957    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Zeng, H. Articles by Xu, X. Search for Related Content PubMed PubMed Citation Articles by Zeng, H. Articles by Xu, X.