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VASCULAR BIOLOGY
Division of Basic Medical Sciences, Ion Channels and Cell Signalling Research Centre, St. George's, University of London, London, United Kingdom
Submitted 30 March 2006 ; accepted in final form 25 July 2006
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONREFERENCES |
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20 mV. In contrast, ERG channel blockade by dofetilide (1 µM) depolarized the resting membrane potential by 8 mV. These data are the first record of ERG channel currents in smooth muscle cells under quasi-physiological conditions that suggest that ERG channels contribute to the resting membrane potential in these cells. vascular smooth muscle; voltage-dependent K+ current; membrane excitability
To assess the functional impact of ERG channels it was necessary to characterize the conductance fully in cells bathed in a solution containing normal physiological K+ (5 mM) and in the absence of either 4-AP or TEA. We therefore used the approach of isolating native ERG currents from other endogenous currents by their distinctive kinetics accompanied by the use of three structurally distinct ERG channel blockers. In addition, studies were undertaken with a novel ERG activator, PD-118057 (33). These studies are the first to characterize ERG channel currents in a smooth muscle cell type under normal ionic conditions and at physiologically relevant membrane potentials, and they revealed that ERG channel currents of significant amplitude were present in most PV myocytes, which appeared to contribute to the resting conductance.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Current and voltage recordings.
Whole cell currents were recorded at room temperature (20–22°C) with either the conventional ruptured patch configuration or the perforated patch variant. To study the voltage-gated K+ current in isolation, EGTA (5 mM) and ATP (3 mM) were included in the pipette solution and recordings were made with the ruptured patch technique. This rationale has been used in a number of studies (see, e.g., Refs. 1, 18, 32) to eliminate any contribution from Ca2+-activated K+ currents, especially of the large-conductance type (BKCa), and ATP-sensitive K+ (KATP) currents to the overall outward conductance. For the perforated patch recordings amphotericin (300 µg/ml) was included in the internal solution and electrical access was monitored by the repetitive application of 10-mV hyperpolarizations until the series resistance was <40 M
. VH in all experiments was –60 mV. Membrane potential recordings were made with the current clamp plus command setting on the amplifier with the perforated patch variant of the whole cell technique. Active responses were evoked by applying 75- to 125-pA current for 2 ms. All recordings were low-pass filtered at 5 kHz and acquired by use of an Axopatch 200B amplifier, Digidata 1322A interface, and pCLAMP (version 9, Axon Instruments, Foster City, CA). Data were analyzed with Clampfit (Axon Instruments), Origin (version 6, Microcal), and Excel (Microsoft). All data were obtained from more than two animals. Results are expressed as means ± SE, and n is the number of cells. Statistical analyses were performed with Student's t-test, and results were considered significant at the P < 0.05 level.
Solutions.
PSS contained (mM) 125 NaCl, 5.4 KCl, 15.4 NaHCO3, 0.33 Na2HPO4, 0.34 KH2PO4, 10 glucose, and 11 HEPES, adjusted to pH 7.4 with NaOH. Enzyme solutions were made up with 100 µM Ca2+ PSS. The bathing (external) solution contained (mM) 126 NaCl, 5 KCl, 1 MgCl2, 0.1 CaCl2, 11 glucose, and 10 HEPES, adjusted to pH 7.2 with NaOH. The pipette (internal) solution contained (mM) 130 KCl, 1 MgCl2, 3 ATP Na+ salt, 0.1 GTP, 10 HEPES, and 5 EGTA, adjusted to pH 7.2 with KOH. Dofetilide and PD-118057 were kind gifts from Pfizer Research. Stock solutions of dofetilide, PD-118057, and E-4031 (Tocris) were prepared in DMSO at 100 mM; recombinant BeKM-1 (Alomone Laboratories) was prepared in distilled H2O at 10 mM. All stocks were stored at –20°C until required. Working concentrations were made up with the external solution immediately before experimentation and continuously perfused by gravity at a rate of 1–2 ml/min. All enzymes and salts were purchased from Sigma and VWR International.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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25% of the peak current. As Fig. 1A shows, application of dofetilide, a blocker of ERG channels at submicromolar concentrations that has a open channel blocking mechanism similar to that of E-4031 (7), also inhibited currents that were transient in nature. However, external application of TEA and 4-AP had a profound effect on the amplitude of the gross voltage-dependent currents evoked from –60 mV (Fig. 1B). For example, the peak current at +40 mV decreased from 12,528 ± 100 pA to 386 ± 60 pA and the sustained outward current at +40 mV was reduced from 1,029 ± 94 pA to 215 ± 342 pA (n = 11). Moreover, the presence of 4-AP and TEA affected the kinetics of the dofetilide-sensitive currents. As Fig. 1C shows, the current sensitive to 1 µM dofetilide in the absence of 4-AP and TEA was relatively well sustained, in contrast to dofetilide-sensitive currents in the presence of 4-AP and TEA (Fig. 1, C and D), resulting in a steady-state current that was markedly less in the presence of the two K+ channel blockers (Fig. 1D). Consequently, these experiments show that the amplitude and appearance of the ERG channel currents recorded in the presence of TEA and 4-AP by Ohya et al. (16) were a significant underestimate of the contribution of ERG channel currents to the membrane conductance. Therefore, for the remainder of the study ERG channel currents were characterized in the absence of TEA and 4-AP.
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) for decay increasing from 19 ± 2 ms at –140 mV to 56 ± 4 ms at –100 mV (n = 28; see also Fig. 5). These values were qualitatively similar to values obtained in PV myocytes bathed in an external solution containing 140 mM K+ (Ref. 16; see also Fig. 5D). These types of kinetics were also similar to those of heterologously expressed ERG channels recorded in symmetrical K+ solutions (see, e.g., Ref. 24). These observations suggested that ERG currents could be recorded in murine PV myocytes even when the cell was bathed in normal external K+.
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8 nM (Fig. 4). The inhibitory effect of BeKM-1 was relatively slow compared with the effects of E-4031 and dofetilide (see Fig. 4C), but the absolute amplitude of the current blocked by each agent was not significantly different. Thus the amplitude of the current blocked by 1 µM E-4031, 1 µM dofetilide, and 100 nM BeKM-1 (i.e., drug-sensitive amplitudes) at –140 mV was 127 ± 13.4 (n = 3), 120.7 ± 22.5 (n = 6), and 157 ± 28 (n = 4) pA, respectively. Furthermore, the activation of the dofetilide-sensitive current at –140 mV exhibited a voltage dependence similar to that of the BeKM-1-sensitive currents [mean V0.5 were –1 ± 3 (n = 6) and –7 ± 7 (n = 4) mV, respectively]. These data show that three structurally different and selective blockers of ERG channels inhibit the hooked inward currents recorded at –140 mV after depolarization to +40 mV.
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Effects of novel ERG activator PD-118057.
Recently, three chemical agents, RPR-260243, PD-118057, and NS-1643, have been developed that activate human (H)ERG channels selectively (4, 8, 33). As HERG is considerably different from the murine ortholog expressed by PV myocytes, we undertook a series of experiments to determine whether the native ERG channel currents in mPV myocytes are also sensitive to PD-118057. Application of PD-118057 at the concentrations used by Zhou et al. (1–10 µM; Ref. 33) had variable effects on the ERG channel currents (Fig. 6). Application of 1 µM PD-118057 inhibited the tail current at –140 mV by 19 ± 7% in three of six cells and produced a small enhancement in the other three cells (mean increase was 8 ± 2%). In contrast, 3 and 10 µM PD-118057 only enhanced the ERG currents. The enhancement of the tail current at –140 mV produced by 3 µM PD-118057 was variable, ranging from 30% to 411% (mean was 129 ± 52%; n = 7), whereas the augmentation produced by 10 µM was more consistent (mean increase was 131 ± 11%; n = 4). The effect of PD-118057 on the inward current was relatively slow to reach a stable level, with the mean time to peak (TTP) produced by 3 µM PD-118057 being 15.5 ± 1 min (n = 6), and was associated with a marked increase in the outward current (Fig. 6Aii). Consistent with the observations of Zhou and colleagues (33), there was no apparent change in the voltage dependence of activation (V0.5 values and slope were –7.6 ± 4.2 mV and 13 ± 3 in the absence and –2.1 ± 5.4 mV and 10 ± 3 in the presence of 3 µM PD-118057, respectively; n = 4). Moreover, PD-118057 appeared to have no consistent effect on either the recovery from inactivation or the deactivation of the murine vascular ERG channel (data not shown). Recovery from channel inactivation (i.e., TTP) was reflected by the rising phase of the inward currents, which at –120 mV was 8.3 ± 0.6 ms in the absence of PD-118057 compared with 8.5 ± 0.8 and 8.2 ± 0.8 ms in the presence of 1 and 3 µM PD-118057, respectively (n = 6–8). For deactivation, for the decay of the current at –120 mV was 34 ± 7 and 36.5 ± 4 ms in the absence and presence of 3 µM PD-118057, respectively (n = 4). However, in contrast to the original study (33), the effects of PD-118057 on native currents in murine PV myocytes were poorly reversed by either 1 µM dofetilide or 100 nM BeKM-1 (see Fig. 6B). Moreover, the enhanced outward current recorded in the presence of PD-118057 (n = 3) was completely resistant to either blocker. To preclude any potential effects of PD-118057 on other voltage-gated K+ conductances, further experiments were performed in the presence of 10 mM TEA and 5 mM 4-AP. Figure 6C shows that in the presence of 4-AP and TEA 10 µM PD-118057 still enhanced the tail current recorded at –140 mV (mean increase was from 94.3 ± 29.5 to 384.0 ± 131.4 pA; 322.8 ± 145.5%, n = 3). In addition, 10 µM PD-118057 converted the transient outward current at +40 mV to a more delayed rectifier profile (see Fig. 6C), with the current at the end of the test step being increased by 482.7 ± 156.0% (n = 3). This enhancement produced by PD-118057 was significantly greater than in the absence of 4-AP and TEA (124.2 ± 10.6%; n = 5, data not shown). As 4-AP and TEA at these concentrations block most K+ channels except ERG, these data suggest that the enhanced current in PD-118057 is not due to the de novo activation of a K+ channel. These data show that the ERG channel activator PD-118057 has marked effects on native currents recorded in the absence and presence of high concentrations of 4-AP and TEA.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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5 mM external K+, negative VH) in cardiomyocytes and neurons (21, 29, 23). However, the only electrophysiological studies on ERG channels in smooth muscle cells have involved cells bathed in a high-K+ (140 mM) solution containing the general K+ channel blockers TEA and 4-AP and using a VH of 0 mV (1, 16). The present study has remedied the situation and represents the first characterization of ERG channels in smooth muscle cells at physiologically relevant potentials. ERG channel currents were identified by their hooked currents at potentials between –140 and –40 mV, which reflect the rapid recovery from inactivation developed at depolarized test pulses followed by a slower, voltage-dependent deactivation. Fitting of these kinetics produced values that were similar to those determined for ERG channel currents recorded in the same cell type under symmetrical K+ conditions by Ohya et al. (16). The existence of ERG channel currents in the present study was confirmed by using three structurally distinct and selective blockers of ERG channels, which all inhibited the evoked current by the same extent. E-4031 and dofetilide have been used in a number of different studies on heterologously expressed and native ERG channels including our previous study (16), and at the concentration used (1 µM) they maximally inhibit ERG channels but still retain a high selectivity for this channel. BeKM-1 is a highly selective peptide inhibitor of ERG channels that has not been studied extensively and that acts preferentially on closed channels (9), in contrast to the open channel blockade shown by dofetilide and E-4031. This agent also abolished the hooked inward currents in mPV myocytes with an IC50 of 8 nM, a value close to that derived for block of heterologously expressed rat ERG1 and ERG2 (respective IC50 values were 19 and 1.5 nM; Ref. 19). Irrespective of the blocker used, the ERG channel current at potentials positive to VH was well sustained in cells bathed in a normal external solution. However, when the bathing solution was enriched by the addition of 5 mM 4-AP and 10 mM TEA sufficient to block most other K+ channels, the ERG channel current was affected markedly. As a consequence the dofetilide-sensitive current became substantially smaller and very transient in nature, consistent with our previous study (16). The inhibitory effect of 4-AP on heterologously expressed ERG channels has been published previously (20), and a full characterization of the effects of 4-AP on the vascular ERG channel was not the goal of this study. However, this observation validates the importance of investigating endogenous ERG currents in the absence of 4-AP and TEA. Moreover, it also raises the possibility that some of the functional effects of 4-AP in particular may be due to partial inhibition of endogenous ERG channels. This facet has extra relevance following the observation in the present study that selective ERG blockers depolarized the RMP significantly, suggesting that ERG channels contribute to the resting conductance. ERG currents were also present when currents were recorded with the perforated patch configuration that minimizes intracellular dialysis and therefore approximates the physiological milieu. However, the degree of dofetilide-sensitive outward current recorded with the perforated patch configuration was considerably less than that recorded with the ruptured patch technique, while the amplitudes and kinetics of the inward currents were identical. This suggests that an intracellular mediator is suppressing outward current flow even though the channels are activated to the same degree (as evinced by the amplitude of the hooked inward currents). As greater outward current will have a considerable effect on membrane stability and consequently vascular reactivity, identification of the molecule in question is an important goal. A number of modulators regulate ERG channels positively, including phosphatidylinositol 4,5-bisphosphate (3), PKC (28), and direct binding of cAMP (5). Alternatively, PKA-dependent phosphorylation decreases current amplitude (5, 27), and PKC inhibits heterologously expressed HERG channels by speeding the rate of deactivation (2). Polyamines are also known to mediate the inward rectification of inward rectifier-type K+ currents (14). Future experiments will address the nature of the intracellular regulators dictating the activity of vascular ERG channels.
Until recently there have been no activators of this conductance, although a multitude of agents that block ERG channels have been reported. However, three selective activators of HERG channels, RPR-260243, PD-118057, and NS-1643, have been developed. This type of agent is being considered as possible treatment for acquired or induced long QT syndrome as well as an effective tool to investigate the biophysical and functional properties of ERG channels (4, 8, 33). To date all the data on ERG activators have been derived from either heterologously expressed ERG channels or action potential recordings in cardiomyocytes. The present study is therefore the first to show effects of an ERG activator, PD-118057, outside of the above systems. Our data showed that PD-118057 increased the amplitude of currents in mPV myocytes, and, similar to the report of Zhou et al. (33), this was not accompanied by a change in the voltage dependence of activation or the rate of channel deactivation or recovery from inactivation. Moreover, PD-118057 markedly hyperpolarized the RMP of mPV myocytes under current clamp and abrogated the active response. The observation that an ERG activator hyperpolarizes the RMP is consistent with our observation that ERG channel blockers depolarize the membrane potential, and data suggest that not only do ERG channels contribute to the resting conductance but activation of vascular ERG channels may be an effective mechanism to suppress membrane excitability.
Interestingly, ERG currents enhanced by PD-118057 were poorly inhibited by the ERG channel blocker dofetilide, which was an efficacious inhibitor of ERG currents under control conditions. Dofetilide (1 µM) inhibited the hooked inward currents recorded at –140 mV by 80% compared with the complete abolition observed in the absence of PD-118057. The reduced effectiveness of dofetilide in the presence of PD-118057 was even more marked at positive potentials, where the current was not inhibited at all. BeKM-1 was equally as ineffective against currents enhanced by PD-118057. These observations were in stark contrast to those of Zhou et al. (33), who saw complete block of currents in the presence of PD-118057, albeit with 10 µM dofetilide, a concentration considerably higher than the IC50 for block of normal HERG currents (7). The reason for this discrepancy is unknown but does not seem to reflect the de novo activation of another K+ conductance, as PD-118057 enhanced currents in cells bathed in 4-AP and TEA at concentrations sufficient to block other K+ channels including Kv1–Kv4 and Ca2+-activated K+ channels. mPV myocytes express mERG1a, which is 99% homologous to hERG, and mERG1b, which has a 342-amino acid NH2-terminal truncation (10, 12, 16). The mERG1b isoform predominates in the mPV, and heterologous expression of this gene results in K+ currents with characteristics distinct from the classic HERG profile (see Ref 12). In the main these are manifest as a considerably faster rate of deactivation. It is not known how PD-118057 or any ERG channel activator affects mERG1b channels. Moreover, the biophysical and pharmacological properties of ERG channel proteins are modified by association with proteins encoded by members of the KCNE gene family, and the mPV expresses KCNE2 and KCNE3 (16). Consequently, identification of the molecular composition of the native ERG channel in vascular myocytes may reveal the reasons for the complex effects of PD-118057 in the present study.
Overall the data of the present study show that ERG channels are active under quasi-physiological conditions and contribute to the RMP. Moreover, activation of these channels by agents such as PD-118057 may be a novel mechanism to suppress changes in membrane excitability. However, the data of the present study revealed that use of PD-118057 should be undertaken with caution. We only have minimal information as to the molecular composition of the ERG channel in mPV myocytes, and future experiments will focus on determining what proteins constitute the endogenous channel.
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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