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1 Bioelectricity Laboratory, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA2 Department of Medicine and Research Center, Montreal Heart Institute and University of Montreal, 5000 Belanger Street, Montreal, Quebec H1T 1C8, Canada
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Abstract |
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30 mV, accelerated deactivation kinetics, prolonged long-closed time, and reduced open probability without affecting single-channel conductance, suggesting a direct channel-blocking effect in addition to well-recognized voltage shifts. HERG subunits expressed in Chinese hamster ovary cells produced channels with properties similar to those of mIKr, except for the more-negative activation of the HERG channels. Despite the abundant expression of mIKr, single-channel events were rarely observed during action-potential clamp and 5 µM E-4031 had no detectable effect on the action potential parameters, confirming that mIKr plays at best a minor role in repolarization of adult mouse cardiomyocytes, probably because the modulatory effects of divalent cations prevent significant mIKr opening under physiological conditions.
(Received 10 December 2003;
accepted after revision 6 January 2004;
first published online 23 January 2004)
Corresponding author G. Koren: Bioelectricity Laboratory, Cardiovascular Division, Brigham and Women's Hospital, 75 Francis St, Boston, MA 02115, USA. Email: gkoren{at}rics.bwh.harvard.edu
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Introduction |
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subunit of the IKr channel is encoded by the human ether-á-go-go-related gene (HERG) (Sanguinetti et al. 1995), which may coassemble with an accessory protein, MiRP1, to form the native IKr channel (Abott et al. 1999). Because of its critical functional role in determining the duration of the action potential and its promiscuous propensity to drug blockade, IKr has become a focal point of research interest. Various mutations in HERG have been linked to abnormal repolarization and long-QT syndromes (LQTs) in humans (Curran et al. 1995). A number of non-cardiac drugs are reported to cause QT prolongation through IKr inhibition (Vandenberg et al. 2001) and are associated with an increased risk of a potentially fatal cardiac arrhythmia known as torsades de pointes, which has resulted in withdrawal from the market of drugs such as grepafloxacin, terfenadine, astemizole and cisapride. In the adult mouse heart, the major delayed rectifier potassium currents involved in repolarization appear to be of different molecular identities. In addition to the prominent transient outward current, a Kv1.5-like current, IK,slow1, and a Kv2.1-like current, IK,slow2, are reported to play important roles (Zhou et al. 1998, 2003; Xu et al. 1999). Of the IKr blockers, E-4031 and dofetilide (Zhou et al. 1998; Wang et al. 1996) are reported to have minimal effects on AP durations of adult mouse ventricular myocytes, and the expression of a dominant negative transgene directed against HERG does not produce prolongation in the QT interval in adult mice (Nerbonne et al. 2001; Babij et al. 1998). Since there is evidence for a key role of IKr in repolarizing the embryonic and neonatal mouse heart (Wang et al. 1996), it has been thought that IKr is minimal or absent in adult mouse cardiomyocytes. Here we report that single IKr channels are abundantly expressed in adult mouse ventricular myocytes. The single-channel properties are characterized and compared with those of channels encoded by HERG in a mammalian cell line. Single-channel analyses reveal that divalent cations modify the voltage dependence of activation as well as the open probability and the rate of deactivation of the channel such that channel openings are minimal under physiological conditions in the mouse heart.
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Methods |
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Ventricular myocytes were isolated from the hearts of adult FVB mice (12–16 weeks, 25–35 g) by standard enzymatic techniques. After the mouse was anaesthetized with enflurane, its heart was removed and perfused for 4–5 min with a nominally calcium-free solution containing (mM): 130 NaCl, 5 KCl, 1.5 MgCl2, 0.33 NaH2PO4, 8 taurine, 5 Hepes, 5 pyruvic acid and 5 glucose. The flow rate was maintained at 2–3 ml min–1 with a peristaltic pump. Subsequently, the heart was perfused for 3–4 min with the same solution to which 0.05% collagenase (Type 1, Sigma), 20–40 µM CaCl2 and 0.1% BSA had been added. The heart was then minced, and cells were dispersed with a glass pipette for 3–5 min in a solution containing (mM): 45 KCl, 70 potassium glutamate, 3 MgSO4, 15 KH2PO4, 16 taurine, 10 Hepes, 0.5 EGTA and 10 glucose (pH 7.38). The cell suspension was filtered through a 100-µm nylon mesh, kept at room temperature for 1 h before transfer to Eagle's minimum essential medium containing 1 mM Ca2+, and used within 6–8 h.
Chinese hamster ovary (CHO-K1) cells stably transfected with HERG channel were cultured in a 35-mm dish with F-12 nutrient mixture (Gibco BRL, no. 1765-047). Recordings were made 48 h after passage.
Electrophysiological recording and data analysis
Whole-cell and single-channel recordings were obtained with an Axopatch-200B amplifier (Axon Instruments, Union City, CA, USA) with standard patch-clamp techniques. Currents were recorded at room temperature (21–23°C). Capacitance and 60–80% of series resistance were routinely compensated. The sampling frequency was 2.5 or 5 kHz; the –3 dB cut-off frequency was 1 kHz. Detailed recording protocols are specified in the text.
For whole-cell recording, pipette resistances were 2–4 M
when filled with (mM): 130 KCl, 5 Mg2-ATP, 5 EGTA, 10 Hepes and 0.5 Tris-GTP; pH was adjusted to 7.2 with KOH. For cell-attached single-channel recording, the pipette resistance was in the range of 8–10 M for pipettes filled with a solution containing (mM): 150 KCl, 1 CaCl2, 1 MgCl2 and 5 Hepes, pH 7.4. In some experiments, divalent cation salts (Ca2+ and Mg2+) were excluded and 10 mM EGTA was added (‘divalent-free solution’). Tyrode solution was used as a standard bath solution and contained (mM): 140 NaCl, 5.4 KCl, 0.33 NaH2PO4, 1 MgCl2, 1 CaCl2, 5 Hepes and 7.5 glucose, pH 7.4. The bath solution for single-channel recording in cardiomyocytes contained (mM): 150 KCl, 10 EGTA, 5 Hepes, 2 K2-ATP and 10 glucose, pH 7.4; for recording in CHO cells, the solution contained 150 KCl, 5 Hepes, 2 MgCl2 and 1 glucose, pH 7.4.
Data were evaluated using pCLAMP8.3 (Axon Instruments) and Origin7.0 (OriginLab Corp.) software, and results are given as means ±S.E.M.
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Results |
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To analyse the properties of native potassium channels in cardiac myocytes, we carried out cell-attached single-channel recordings in isolated mouse cardiomyocytes. As shown in Fig. 1, two types of potassium channels were typically seen in our recordings. The first channel showed a typical inward rectifier property (IK1), opened at negative but not positive potentials, and had a slope conductance of 30 pS. The other type of channel was more readily elicited at negative potentials after a positive depolarization and showed a much smaller conductance. As illustrated later, this small channel demonstrated properties closely resembling those of IKr reported in rabbit (Shibasaki, 1987; Veldkamp et al. 1993), guinea-pig (Sanguinetti & Jurkiewicz, 1990) and human (Veldkamp et al. 1995) myocytes and the HERG channel in Xenopus oocytes (Zou et al. 1997). Therefore, we will refer to it as mouse IKr (mIKr). To our surprise, mIKr channels were observed very frequently, appearing in 158 (50.1%) of 314 patches as compared with Kir channels, which were seen in 131 (41.7%) of 314 patches.
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fast and slow were 37.1 ± 3.5 ms (n= 5) and 326.1 ± 36.7 ms (n= 5), respectively. In the absence of divalent cations, the mean fast and slow were slower: 70.8 ± 8.7 ms (n= 3) and 969.3 ± 207.2 ms (n= 3), respectively. Of note, the ensemble-averaged currents in six patches could not be fitted because the currents persisted for several minutes.
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0 mV due to fast voltage-dependent inactivation that results in a negative slope conductance at positive voltages (Sanguinetti & Jurkiewicz 1990, 1991; Trudeau et al. 1995; Smith et al. 1996; Spector et al. 1996). Figure 4 shows IKr channel activity following steps from a holding potential of –80 mV to a series of test potentials between –110 mV and +70 mV, followed by a step to –60 mV. In the presence of divalent cations, depolarization-induced channel openings were first observed at –30 mV (Fig. 4A), while in divalent-free solution they were evident even at –70 mV (Fig. 4B). These results indicate that the addition of divalent cations shifted the threshold of mIKr activation to a more positive potential. Upon stepping to –60 mV, channel activity was observed following all the prepulses between –110 and +70 mV in the absence of divalent cations but were evident only after potentials positive to –10 mV in the presence of divalent cations (Fig. 4A). The NPo of the ‘tail currents’ at –60 mV was voltage-dependent and was shifted to more-positive potentials in the presence of divalent cations in the pipette solution. The mean half-activation voltage (V1/2) was –14.8 mV in the presence of divalent cations, and the slope factor is 8.0 mV; in the absence of divalent cations the V1/2 and slope factor were –43.1 mV and 25.6 mV, respectively.
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Thus far, we have described a single channel in mice that possesses biophysical properties resembling those of IKr channels recorded in other species and have explored the effect of extracellular divalent cations on its single-channel behaviour. To further verify that the channel we observed was indeed IKr, we examined the effect of E-4031, a specific blocker of IKr, on the single-channel activity. As shown in Fig. 7, E-4031 inhibited channel events during both depolarization and repolarization. Complete blockade by 1 µM E-4031 was seen within 1 min of application. In 2 of 15 patches, channel activities partially recovered after a 5-min washout period. In the other 13 patches that could be followed for 5–10-min washout periods, the effect of E-4031 was irreversible.
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Previous results from other laboratories demonstrated single-channel activities (IKr/HERG) could only be observed during repolarization after the channel had been activated at high voltages (Veldkamp et al. 1995) even under divalent-free conditions (Veldkamp et al. 1993; Zou et al. 1997). This contrasts with our observations of mIKr openings following both depolarization and repolarization. We therefore examined the single-channel activity of HERG stably expressed in a CHO cell line under similar recording conditions to compare its properties with those of mIKr. As shown in Fig. 9 (comparable format to Fig. 2), single HERG channel events were observed at all repolarizing potentials (–120 to –20 mV) following the +60 mV prepulse. As for mIKr channels, the presence of divalent cations did not affect the slope conductance of the HERG channel (13.44 ± 0.34 pS, n= 9, with divalent versus 13.39 ± 0.50 pS, n= 15, divalent-free). With the standard protocol shown in Fig. 4, we also observed that the HERG channel could be activated during depolarization and repolarization, a phenomenon like that observed in the mIKr channel, but activated at more negative potentials than mIKr channels (Fig. 10). The mean half-activation voltage (V1/2) was –33.82 mV in the presence of divalent cations, and the slop factor is 7.14 mV; in the absence of divalent cation the V1/2 and slop factor are –65.93 mV and 12.18 mV, respectively. Again, effects of divalent cations on HERG channels were similar to those on mIKr; i.e. positively shifted by 30 mV. Further continuous recordings proved that HERG channels could be activated as far negative as –110 mV (found in 50% patches, n= 21). In Fig. 11, we first held the membrane at –120 mV for at least 20 s and then gradually stepped to less negative potentials. The channel opened after a 16 s delay following the potential change to –110 mV. After the channel was closed at –110 mV, the membrane potential was stepped to –100 mV, which triggered second openings after a 12.5 s latency. At +60 mV, the channel opened sparsely, but multiple channels were seen upon repolarization to –110 mV. Similar to the activation of mIKr channel, activation of the HERG channel was also slow upon depolarization, but fast upon repolarization.
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Discussion |
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Whole-cell experiments examining the properties of IKr/HERG have demonstrated that extracellular divalent cations reduce the current's amplitude, shifted its activation, and slowed its inactivation (Ho et al. 1996, 1998, 1999; Paquette et al. 1998; Johnson et al. 1999; Song et al. 1999). Our single-channel data are consistent with the findings of macroscopic studies and further characterize the effect of Ca2+/Mg2+ on the IKr/HERG channel. We found that physiological concentrations of extracellular Ca2+/Mg2+ caused 30 mV positive shift in activation. Moreover, extracellular Ca2+ and Mg2+ reduced the open probability through prolongation of a long closed time but did not affect the conductance of the IKr/HERG channel. These results indicate that extracellular divalent cations may exert a direct effect on the voltage sensor of the channel. However, it is worth noting that Ca2+ and Mg2+ may not necessarily exert their effects on the IKr channel in the same manner, either quantitatively or qualitatively, and thus further studies investigating their individual effects are warranted.
When HERG channels were expressed in CHO cell, they showed similar behaviour to mIKr channels in conductance, activation and deactivation. However, HERG channels activated at more negative potential than mIKr channels. These results suggest that, in native myocytes, the IKr channel may be regulated by additional subunits (e.g. MiRP1 and/or minK) that modify the threshold of activation. Alternatively, PiP2 might play a role in determining the threshold, since it shifts activation and increases open probability (Bian et al. 2001).
Previous single-channel studies of IKr in rabbit and human ventricular myocytes (Veldkamp et al. 1993, 1995) or the HERG channel in Xenopus oocytes (Zou et al. 1997; Kiehn et al. 1999) indicated that IKr/HERG is a repolarization-activated channel, since no single-channel openings were observed while the potentials were held at values more negative than –70 mV. However, we find that single-channel openings of mIKr and HERG can be seen at quite negative holding potentials, especially after divalent cations are removed from the extracellular solution. This notion is consistent with the whole-cell recording of the IKr/HERG current. The failure of the former studies to observe single-channel openings at negative holding potentials might be attributable in part to the presence of divalent cations in the pipette solution, since the addition of Ca2+/Mg2+ dramatically shifts activation. Another potential explanation could be the short holding time, since the activation latency was sometimes quite long at negative potentials. Alternatively, the difference could also be attributed to the presence of species-specific subunits, or differences in expression systems (Abbott et al. 1999; McDonald et al. 1997).
Contrary to the early dofetilide-binding findings of an absence of IKr on the membrane of adult mouse ventricular myocytes (Wang et al. 1996), we found that IKr was expressed abundantly in single-channel recordings. Our data correlate well with recent observations documenting robust expression of mERG transcript and polypeptide in the mouse heart (London et al. 1997; Lees-Miller et al. 1997; Pond et al. 2000; Pond & Nerbonne, 2001). However, at the whole-cell level when physiological concentrations of Ca2+ and Mg2+ are present, mIKr appears to play a minimal role in cardiac repolarization, as confirmed by pharmacological studies with dofetilide (Wang et al. 1996) and E-4031 (Fig. 8E). Indeed, the current density of mIKr (0.23 pA pF–1 at +50 mV for 1 s) was 50- to 100-fold less than those of the dominant Ito (25–35 pA pF–1) and IK,slow (15–20 pA pF–1) (Zhou et al. 1998,2003; Xu et al. 1999; Guo et al. 1999). It is highly possible that the effects of extracellular Ca2+/Mg2+ (e.g. shifting the activation and reducing the open probability) have made activation of mIKr so difficult as to prevent its playing a role in repolarization during the extremely short action-potential duration above its activation threshold. Supporting this notion is our failure to observe any single-channel activity using an action potential waveform to stimulate the membrane patch in the presence of Ca2+/Mg2+ but our ability to detect channel events when extracellular Ca2+/Mg2+ was removed (see Fig. 8F).
Since single-channel opening of the IKr/HERG channel could be seen at negative potentials close to the K+ equilibrium potential, IKr/HERG might also contribute to maintenance of the resting membrane potential. Although this may not be important to ventricular myocytes, in which resting potential is dominated by IK1 (Kir channel), it might be important for maintenance of maximal resting membrane potential of pacemaker cells, such as sino-atrial node pacemaker cells, which are thought to be rich in the IKr channel (Ito & Ono, 1995; Matsuura et al. 2002; Noma et al. 1984) but lacking in the Kir channel (Noma et al. 1984; Nathan, 1986). Interestingly, a recent study demonstrated episodes of sinus bradycardia related to functional deficiency of IKr channels in pacemaker cells in ERG1 B knock-out mice (Lees-Miller et al. 2003). Additionally, we speculate that mIKr may serve as a divalent cation sensor in cardiomyocytes and that depletion of cations in microdomains outside the cell may result in the activation of mIKr at negative potentials and influence membrane potential.
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, n= 27).
