Centre National de la Recherche Scientifique, Unité Mixte de Recherche 6542, Faculté des Sciences, Université de Tours, 37041 Tours Cedex, France
Submitted 11 April 2003 ; accepted in final form 18 August 2003
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ABSTRACT |
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heart; calcium current; low-voltage activation
Ca2+-induced inactivation of L-type Ca2+ channels arises from activation of calmodulin bound to the intracellular COOH terminus of the 1-subunit of the channel (3, 19). It has been suggested that inactivation of the L-type Ca2+ channel, whether by voltage or Ca2+, is an absorptive state; that is, once the channel has opened in response to depolarization and subsequently assumed an inactivated state, this state is irreversible during continued depolarization and is reversed only on hyperpolarization. Although reasonable for the molecular changes associated with voltage-dependent inactivation, this is not consistent with the known interaction between Ca2+ and calmodulin, which is readily reversible and dependent only upon Ca2+ concentration. Thus Ca2+-dependent inactivation should reflect the increase of intracellular Ca2+ concentration after Ca2+ influx and CICR and the subsequent reduction due to Ca2+ diffusion and buffering, reuptake, and efflux by intracellular buffers, sarco/endoplasmic reticulum Ca2+-ATPase (SERCA), and the Na+/Ca2+ exchanger, respectively.
However, the idea that Ca2+ is the only trigger for SR Ca2+ release (SRCR) in cardiac muscle has been challenged by the suggestion that voltage-gated SR Ca2+ release (VSRM) (see Ref. 14 for recent review) may also occur in these cells. It has been proposed that such release is activated at voltages negative to the threshold for activation of ICaL, so that Ca2+ release from the SR may coincide with, or even precede, activation of ICaL, which may have important implications for Ca2+-dependent inactivation of ICaL. It has, however, also been suggested that VSRM is an artifact of particular in vitro conditions (44), and alternative means of evoking low-voltage CICR have been proposed (11, 35, 40): it is possible that ICaL is activated at low voltages in the presence of increased cAMP concentrations (32), which are required to demonstrate VSRM.
The initial objective of this study was to characterize the relationship between the activation of ICaL and CICR and the consequent Ca2+-induced inactivation of ICaL. In particular, we were interested in the early, rapid, and reversible inactivation of ICaL (9, 39); this multiphasic decay can be blocked by ryanodine and thus appears to be due to SRCR, which suggests that Ca2+-induced inactivation as distinct from voltage-dependent inactivation might not be an absorbing state. We also found that in the presence of isoproterenol, the degree of Ca2+-induced inactivation caused by SR depended not only upon the activation voltage of ICaL but also upon the voltage from which ICaL was stimulated. This appeared to be due to CICR evoked by ICaL at negative potentials.
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METHODS |
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A plastic petri dish containing isolated myocytes was placed on the stage of an Olympus CK2 inverted microscope. The myocytes were superfused with experimental solutions via a system of parallel tubes positioned adjacent to the cells. Fluid flow was maintained by gravity from syringe barrel reservoirs, and the exchange of solutions was achieved by manual displacement of the tubes. Solution exchange around the myocyte was estimated to be complete in 4-5 s. All experiments were conducted at room temperature (23°C).
Experimental procedures. Whole cell current voltage-clamp experiments were conducted using an Axon Instruments 202A patch-clamp amplifier in resistive feedback mode (Axon Instruments). Pipettes were fabricated from thin-walled borosilicate glass capillary tubes (Clark Electro-medical Instruments, Pangbourne, England) with a Narishige PP7 double-stage puller (Narishige Instruments, Tokyo, Japan). Pipettes were coated with Sylgard (Dow Corning) and then heat polished. Finished pipettes had a resistance of <2 M when filled with standard intracellular solution. Experimental voltage-clamp protocols and data acquisition were controlled with Acquis1 software (Dipsi Industrie, Chatillon, France) installed on a 386-20 PC computer. Data were filtered at either 1 or 2 kHz and acquired at 2 or 5 kHz, respectively. Data analysis was performed with either Acquis1 or Origin 4.1 (Microcal Software). Results are shown as means of data obtained from n myocytes with bars representing SE when these are larger than their respective symbol. Cell capacitance and series resistance were compensated (
80%) with the Axon Instruments amplifier so that the maximum voltage error was <3 mV. Only cell current recordings with a series resistance of <5 M
were accepted for study. Cell currents are expressed in cell current density, pA/pF. Once the whole cell configuration of the patch-clamp cell current recording technique (18) had been achieved, isolated myocytes were voltage clamped at -80 mV. Voltage-clamp protocols were delivered to the cells from this holding potential.
Experimental solutions. The standard extracellular solution used to fill the petri dishes and store myocytes contained (in mM) 140 NaCl, 5 KCl, 2 CaCl2, 1 MgCl2, 10 glucose, and 10 HEPES, pH 7.4, with NaOH. TTX citrate salt, 10 µM (from either Alomone Labs, Jerusalem, Israel, or Latoxan, Valence, France) was added to this standard solution when required. In some experiments, extracellular NaCl was replaced by an equimolar amount of N-methyl-D-glucamine (NMDG), and the pH was adjusted with HCl. The standard intracellular solution used to fill the patch pipettes contained (in mM) 140 KCl, 10 NaCl, 5 EGTA-KOH, 1.4 MgCl2, 0.1 CaCl2, 2 ATP-Mg2+, 10 glucose, and 10 HEPES, pH 7.3, with KOH. The estimated free concentrations of Mg2+ and Ca2+ in this solution were 1 mM and 1 nM, respectively. One series of experiments (Fig. 2A) was conducted with Na+- and K+-free solutions where extracellular Na+ was replaced by 140 mM TEA-Cl, and K+ was replaced by 5 mM CsCl2, and intracellular K+ and Na+ were replaced by 100 mM CsCl2 and 40 mM TEA-Cl. In experiments in which -adrenergic stimulation used, the pipette solutions also contained 100 µM GTP. Cadmium, barium, and nickel were added to extracellular solutions as their chloride salts. Isoproterenol was prepared daily as a 100-µM stock solution in distilled water and added to extracellular solutions to give a final concentration of 100 nM. Ryanodine was dissolved as a 2-mM stock solution in distilled water and added to extracellular solution to give a final concentration of 10 µM. Forskolin was dissolved as a 10-mM stock solution in DMSO and added to extracellular solution to give a final concentration of 10 µM. When the effects of forskolin were tested, an equivalent amount of vehicle was added to all experimental solutions.
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RESULTS |
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The effect of conditioning voltage upon ICaL was analyzed by recording the amplitude and the rate of decay of ICaL at -20 mV (Fig. 3A) and +20 mV (Fig. 3B) after voltage steps to between -70 and -40 mV. Maximal ICaL amplitude at either voltage was recorded from a conditioning voltage of -50 mV, and all data were therefore normalized to this value. The amplitude of ICaL was reduced when conditioning voltages were positive to -50 mV. This reflects the onset of voltage-dependent inactivation of ICaL (31) and was independent of the experimental conditions. On the other hand, the effect of conditioning voltages negative to -50 mV depended upon the experimental condition. In basal conditions, irrespective of the presence (circles) or absence (squares) of ryanodine, the amplitude and the rate of decay of ICaL were essentially unchanged by conditioning voltages negative to -50 mV. But, in isoproterenol (triangles) the amplitude of ICaL was progressively reduced and the rate of decay of the current progressively increased with conditioning voltages negative to -50 mV. These effects were abolished by ryanodine (inverted triangles).
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These results could arise from an effect of conditioning voltage or from the repetitive application of voltage-clamp stimuli (12). If repetitive stimulation were responsible for the increase in the amplitude of ICaL and the reduction of its rate of decay, this would occur irrespective of the order of presentation of the conditioning voltage. Figure 4A illustrates results obtained when conditioning voltage steps were applied sequentially from -65 to -40 mV, and Fig. 4B illustrates results obtained when conditioning voltage steps were applied sequentially from -40 to -65 mV. In both cases, ICaL evoked from -60 mV showed multiphasic decay, whereas ICaL evoked from -40 mV showed sequential decay. There was no difference in the relationship between conditioning voltage and either peak current amplitude (Fig. 4C) or rate of inactivation (Fig. 4D) when conditioning voltage steps were applied sequentially from -40 to -65 mV (open symbols) or from -65 to -40 mV (closed symbols). A second test of the effect of repetitive stimulation of ICaL applied a stimulus from -65 mV to -20 mV 14 times every 6 s. Neither the amplitude nor the rate of inactivation of ICaL was influenced by repetitive stimuli at this frequency (n = 8). It is concluded that the effects of conditioning voltage upon the amplitude and rate of inactivation of ICaL did not result from repetitive application of voltage-clamp stimuli or repetitive activation of ICaL. Therefore ICaL amplitude and rate of decay were influenced by conditioning membrane voltages that were apparently subthreshold for its activation and inactivation.
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Calcium release from the SR and inactivation of ICaL. The experiments shown in Fig. 5 addressed two issues. The first concerned the multiphasic decay of ICaL observed during voltage steps to negative voltages during -adrenergic stimulation (Figs. 1, 2, and 4). Recovery of ICaL from Ca2+-induced inactivation during sustained depolarization has not been a frequent observation (9, 39) but implies that Ca2+-induced inactivation is not an absorptive state. This led us to question whether SR might be capable of
inactivating
ICaL before the current had been activated. The second issue concerned the loss of the multiphasic decay and increase in amplitude observed with more positive conditioning voltages or ryanodine (Fig. 1B), which suggests that triggering SRCR might relieve a subsequent ICaL from inhibition by its own CICR.
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Figure 5A represents the standard conditions for this series of experiments and illustrates results obtained from the application of a double pulse voltage-clamp protocol consisting of 500-ms prepulse voltage steps, a 10-ms interval, and a test pulse, so that there were 510 ms between the onset of the prepulse voltage step and the onset of the test pulse. Although this particular series of cells showed little or no facilitation of the amplitude of ICaL, a prepulse to -40 mV, without inducing inactivation, resulted in reduced decay of ICaL. This effect was abolished by ryanodine.
Figure 5B illustrates results obtained using 50-ms prepulse voltage steps, so that the onset of the prepulse voltage step was separated from the onset of the test pulse by 60 ms. These short prepulse voltage steps applied to between -55 and -40 mV resulted in a clear reduction in amplitude of the following ICaL. This effect was abolished by ryanodine. This result strongly suggests that voltage steps to between -55 and -40 mV were associated with SRCR, which inhibited sarcolemmal Ca2+ channels before their activation. That neither Ca2+ influx during, nor membrane voltage of, the prepulse voltage step was responsible for the reduction of the following ICaL was shown by their lack of effect in the presence of ryanodine.
Figure 5C illustrates results obtained when short prepulse voltage steps were situated with their leading edge 510 ms before the onset of the test voltage pulse. In the presence of isoproterenol alone, short voltage steps to -50 mV and more positive voltages provoked an increase in the amplitude of the following ICaL and reduced its decay. These effects were abolished by ryanodine. It is concluded from these results that triggering SRCR during one voltage step decreased inhibition and inactivation of the following ICaL due to its own CICR (Figs. 5, A and C). Whether this resulted from inactivation of the SRCR mechanism (22), of the ryanodine receptors (38), or transient exhaustion of the junctional SR (1, 12, 13) remains to be determined.
These data also show that the triggering of SRCR has different effects upon ICaL depending upon the temporal relation between the increase in intracellular Ca2+ and the activation of ICaL (Figs. 5, B and C).
The low-voltage trigger for Ca2+ release from the SR? The data shown in Figs. 1 and 5 suggest SRCR at membrane voltage steps that are normally considered too negative to activate ICaL and consequent CICR (22) but which could be explained by VSRM (14). We therefore investigated events during low-voltage steps to determine what might be responsible for triggering SRCR.
Figure 6A shows currents triggered from -70 mV in the presence of isoproterenol. A voltage step to -40 mV evoked a small transient inward current. The I-V relationship of currents evoked from -70 mV shows a clear inflection of inward currents between -50 and -20 mV in addition to ICaL.
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The nature of this low-voltage-activated transient inward current was examined (Fig. 6B). The availability of this current was tested using a double pulse voltage-clamp protocol with a test pulse to -40 mV. When prepulse voltage steps were applied to membrane potentials more negative than -70 mV, there was a considerable increase in the amplitude of the transient low-voltage-activated current recorded at -40 mV (Fig. 6B and filled symbols). The amplitude of this current did not saturate even with prepulse voltage steps as negative as -90 mV. Although all bathing solutions contained 10 µM TTX, it was decided to test whether this large transient inward current might depend upon extracellular Na+. When extracellular Na+ was replaced by NMDG, the transient inward current recorded at -40 mV was abolished (Fig. 6B and open squares) and could not be recovered by prior voltage steps to values as negative as -90 mV. It is concluded that this low-voltage-activated transient inward current corresponded to INa+ that had not been entirely blocked by the inclusion of 10 µM TTX in the solutions bathing the cells.
The next series of experiments was to investigate whether this residual TTX-insensitive portion of INa+ might be responsible for triggering low-voltage-associated SRCR. The three experimental protocols used to investigate the effect of prior voltage duration and temporal position upon ICaL (Fig. 5) were applied to myocytes bathed first in normal Na+-containing solution containing TTX and then in extracellular solution in which Na+ had been replaced by NMDG. Neither the 500-ms availability curve (n = 9), the prior low-voltage reduction of ICaL (n = 7), nor the 500-ms leading edge prior voltage facilitation of ICaL (n = 8) were affected by the removal of extracellular Na+ (data not shown). Thus it appears that INa+ is not responsible for low-voltage-associated SRCR.
In the following experiments (Figs. 7 and 8), cells were bathed in Na+-free, NMDG-rich extracellular solution. Cells were exposed to this solution for only as long as required to apply the different voltage-clamp protocols; otherwise, they were superfused with the standard Na+-rich extracellular solution. Insufficient time was allowed for the absence of extracellular Na+ to influence the -adrenergic response (6, 20).
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Guinea pig ventricular myocytes express the low-voltage-activated transient T-type Ca2+ current (5), and during -adrenergic stimulation, INa+ might allow Ca2+ influx via
slip-mode
conductance (35). Either of these currents could cause Ca2+ entry at negative potentials and, hence, trigger SRCR, thus influencing ICaL. Figure 7 shows experiments designed to test for the presence of these currents. The voltage-clamp protocol promotes the detection of the T-type Ca2+ current (5, 40), whereas the experimental conditions promote slip-mode conductance of INa+ (35). Whether voltage steps were applied from conditioning voltages of -50, -90, or -110 mV, no transient inward currents could be detected (Fig. 7A) and no inflection of the total I-V relation could be seen in the low-voltage range (Fig. 7B). Because neither ICaT nor slip-mode Ca2+ conductance via INa+ could be detected under these conditions, it is concluded that these currents would not have provoked CICR to account for the effects of low-voltage-associated SRCR upon ICaL.
Another possible source of low-voltage gated Ca2+ entry that could trigger SRCR is ICaTTX (2, 11, 21). The presence of ICaTTX was investigated in experiments similar to those shown in Fig. 7 in the presence and absence of 10 µM TTX. No TTX-sensitive current could be distinguished in the recordings (n = 3), so it is unlikely that ICaTTX could be responsible for low-voltage-associated SRCR.
It remained to test for the presence of ICaL at low voltages during -adrenergic stimulation. ICaL was detected by conducting experiments in extracellular solutions that contained either 2 mM CaCl2 and 1 mM MgCl2 (Fig. 8Aa, +Ca2+, and squares in Fig. 8B) or 3 mM MgCl2 and 250 µM EGTA.NaOH (Fig. 8Ab, -Ca2+, and circles in Fig. 8B). ICaL was abolished by replacement of extracellular Ca2+ with Mg2+ (Fig. 8A) without effect upon membrane surface charge screening. In the absence of extracellular Ca2+, the I-V relation of isolated ventricular myocytes showed the N-shape characteristic of the background K+ current IK1 (Fig. 8B). Close comparison of current records obtained in the presence and absence of extracellular Ca2+ (Fig. 8C) revealed that steps to membrane potentials positive to -50 mV resulted in essentially time-independent Ca2+ currents superimposed upon IK1. Although these currents did not attain a level that corresponded to the gross inward current carried by Ca2+ when voltage was stepped to -35 mV, the difference between the currents recorded at -45 and -40 mV in the presence and absence of Ca2+ represents a net influx of Ca2+.
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DISCUSSION |
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Experimental approach used. It is well known that Ca2+-dependent inactivation of ICaL in cardiac cells is due to Ca2+ flowing via the channel and Ca2+ release by the SR (1, 9, 36, 39). The presence of a slow Ca2+ buffer (EGTA) appears not to interfere with the local Ca2+ signaling between L-type Ca2+ channels and ryanodine receptors, which takes place in a restricted diffusion space (24, 3, 12, 36). In a previous study, we showed that by using a faster Ca2+ chelator (BAPTA), such local Ca2+ signaling is stopped (9). Furthermore, using confocal microscopy, Song et al. (41) showed that in the presence of 10 mM EGTA, ICaL-induced release of Ca2+ in the dyadic space, (intracellular Ca2+ recorded using Oregon Green 5N), providing direct evidence that Ca2+ is released in the dyadic space in the presence of EGTA.
In recent years, it has been shown that Ca2+-dependent inactivation of the L-type calcium channel is due to Ca2+ binding to calmodulin tethered to the COOH terminus of the channel (see Ref. 33 for review). In the present study, we used Ca2+-dependent inactivation of ICaL as an assay of Ca2+ binding to this calmodulin, as other investigators use contraction as an assay of Ca2+ binding to troponin C.
Fast and reversible calcium-dependent inactivation of ICaL. Previous work has shown that the decay of ICaL in cardiac myocytes can be multiphasic (9, 39). The evidence strongly suggests that multiphasic decay of ICaL results from SRCR because it is blocked by ryanodine. Multiphasic decay did not seem to result from the accumulation or the depletion of Ca2+ because the decay of ICaL was sequential in the presence of ryanodine and when ICaL was carried by Ba2+; in both conditions, the current was larger and accumulation or depletion would have been expected to be greater. It did not seem to be associated with activation of IClCa (47, 48, 49, 50), first, because an equivalent and opposite current was not observed at membrane potentials, which were on the other side of the equilibrium potential for chloride, and second, because activation of ICl under the experimental conditions used here evoked an inward rather that an outward current. Multiphasic decay of ICaL could be observed in the absence of extracellular and intracellular Na+, which inhibits Na+-Ca2+ exchange (9), arguing against the superposition of Na+-Ca2+ exchange current upon ICaL. We propose that multiphasic decay of ICaL in cardiac myocytes reflects the voltage dependence of the gain between Ca2+ influx and SRCR predicted by local control theory (42) and supported by direct observation (34). Analysis of the rate of decay of ICaL (Fig. 3) showed that multiphasic decay represents one extreme of the general process of the acceleration of inactivation of ICaL by SRCR (1, 9, 29, 36, 37, 39).
Although abolition of the overshoot
of inactivation of ICaL was the most evident demonstration of the effects of conditioning voltage steps and ryanodine, the equivalent of increased current amplitude and reduced rate of decay were found in ICaL with simpler forms of decay (Fig. 3). Thus the effect of conditioning voltage on the current was not a characteristic confined to a particular set of conditions. The particular effect of SRCR depended upon its temporal relation with the activation of ICaL. Thus release of Ca2+ just before the activation of ICaL inhibited the current (Fig. 5B) in a manner reminiscent of the inhibitory effects of Ca2+ release evoked either by caffeine (1, 28) or illumination of caged compounds (8, 17). The release of Ca2+
500 ms before activation of the current liberated the following ICaL from CICR and enhanced ICaL amplitude with reduced decay (Fig. 5C) in a manner similar to frequency dependent facilitation of ICaL (12, 25). This could reflect the refractory period for SRCR that may result either from transient reduction of junctional SR Ca2+ content (1, 12, 13) and/or refractoriness in the behavior of ryanodine receptors (38). Alternatively, conditioning voltage steps may have inactivated the VSRM mechanism (22).
Possible mechanism of low-voltage-triggering Ca2+ release. The importance of coordinating Ca2+ influx via sarcolemmal Ca2+ channels and release of Ca2+ from the SR is indicated by studies that show SRCR can limit not only Ca2+ entry into the cell but also reconfigure the contribution of ICaL to the ventricular action potential (12, 29). In this context, the potential importance of VSRM (14) is evident: the simultaneous rather that the sequential occurrence of Ca2+ influx and Ca2+ release could severely impair the function of ICaL. The mechanism of low-voltage-activated release of Ca2+ from the SR has been controversial. The evidence for a purely voltage-dependent release mechanism has been recently challenged by experiments that could not record SRCR in the absence of ICaL (16, 45). In the present study, a number of candidates for low-voltage-activated Ca2+ entry to provoke CICR were tested, but neither ICaT (5, 40), ICaTTX (11, 21), nor slip mode Ca2+ current through INa+ (35) could be recorded under experimental conditions where prior voltage clearly influenced ICaL in a ryanodine-dependent manner. On the other hand, ICaL was activated at voltages negative to -40 mV in the presence of the -adrenergic agonist isoproterenol (Fig. 8). These currents were small and essentially time independent, in contrast to the transient current reported in cat myocytes (32) but similar to those recorded in the rat and rabbit (16, 43). However, opening of single L-type Ca2+ channels, particularly with the large driving force at such negative voltages, can provoke CICR (7, 10, 23, 34, 41, 46).
In conclusion, the data in this study do not resolve the controversy between CICR and VSRM as mechanisms causing SR Ca2+ release (4). The data do, however, contribute to the developing consensus of experimental evidence (16, 45) that suggests that VSRM may be accounted for by CICR evoked by activation of ICaL at negative potentials.
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ACKNOWLEDGMENTS |
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Present addresses: F. Brette, School of Biomedical Sciences, University of Leeds, UK; J.-Y. Le Guennec, INSERM EMI 0211, Faculté de Médicine, Université de Tours, France.
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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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