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MEMBRANE TRANSPORTERS, ION CHANNELS, AND PUMPS
1Cardiac Membrane Research Laboratory, Simon Fraser University, Burnaby; 2Cardiovascular Sciences, Child and Family Research Institute, Vancouver; 3Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, British Columbia, Canada; and 4Laboratorio de Fisiología Celular, Cardiología, Hospital de Sant Pau, Barcelona, Spain
Submitted 11 May 2005 ; accepted in final form 5 January 2006
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ABSTRACT |
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cardiac ontogeny; cardiac excitation-contraction coupling; calcium homeostasis
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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Whole cell perforated patch-clamp voltage.
A whole cell amphotericin-perforated voltage-clamp technique was used at room temperature as described previously (17). The internal pipette solution contained (in mM) 110 CsCl, 5 MgATP, 1 MgCl2, 20 tetraethylammonium (TEA), 5 Na2 phosphocreatine, and 10 HEPES at pH 7.1 adjusted with CsOH. The standard external solution contained (in mM) 130 NaCl, 5 CsCl, 1 MgCl2, 2.0 CaCl2, 5 Na+-pyruvate, 10 glucose, and 10 HEPES at pH 7.4 adjusted with NaOH. In some experiments, the cells were perfused with a nominally Ca2+-free solution (referred to herein as 0 mM) or with different internal and external Na+ concentrations ([Na+]i and [Na+]o, respectively, and 125 and 14 mM, respectively, with the difference from standard external solution being replaced with CsCl). Only cells in which the access resistance was <20 M
were used in these experiments.
Measurement of Ca2+ fluorescence.
Cytosolic Ca2+ concentration ([Ca2+]i) was measured using the fluorescent Ca2+ indicator fluo-3 AM as described previously (17). F0 was assumed to be the difference between background fluorescence determined in the absence and presence of a cell in the area of measurement. 
F is the increment measured from baseline or the background fluorescence in the presence of a cell-free area. Fmax was the fluorescence acquired after the cell was depolarized to +200 mV for 10–20 s to flood the cytosol with Ca2+ at the end of each experiment.
Electron microscopy.
Images of the cross sections of the ventricular muscle myocytes were obtained with a Phillips 300 electron microscope as described previously (13). Briefly, each heart was perfused for 15 min using a Langendorff apparatus at age-appropriate perfusion speeds (37°C). After initial fixation, the hearts were removed from the Langendorff apparatus. The ventricle was trimmed into small blocks of 
0.5 x 0.5 x 0.5 mm and immersed in the fixative for 2 h at 4°C on a shaker. The blocks were then washed three times in 0.1 M sodium cacodylate (10 min each). In the process of secondary fixation, the blocks were placed into 1% OsO4-0.1 M sodium cacodylate buffer for 2 h and then were washed three times with distilled water (10 min each). The blocks were then treated with 1% uranyl acetate for 1 h (en bloc staining), followed by being washed with distilled water. Increasing concentrations of ethanol (50%, 70%, 80%, 90%, and 95%) were used (10 min each) in the process of dehydration. Ethanol (100%) and propylene oxide were used (three 10-min washes each) for the final process of dehydration. The blocks were infiltrated overnight in the resin (TAAB 812) and then embedded in molds and polymerized in an oven at 60°C for 8–10 h. The embedded blocks were sectioned on a microtome using a diamond knife and placed on 400-mesh copper grids. The section thickness was 80 nm. The sections were then stained with 1% uranyl acetate (4 min) and Reynolds lead citrate (3 min) and imaged using a Phillips 300 electron microscope. Twenty-five sections from each of three hearts for each of two age groups (3d and 56d) were used for statistical analysis.
Data analysis.
Data are means ± SE. The statistical significance of the results was tested using one-way ANOVA with SPSS version 11.0 software (SPSS, Chicago, IL) or Student's t-test for paired or unpaired samples. Post hoc tests were performed using Tukey's multiple-comparison test. P 
0.05 was considered statistically significant.
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RESULTS |
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F/F0) during 60-s loadSR (data not shown).
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Increased [Ca2+]i as consequence of SOCE.
The results shown in Figs. 1 and 2 suggest that loadSR at rest occurs through SOCE or nonselective cation channels (NSCCs). To test this hypothesis, a classical approach based on readdition of 2 mM [Ca2+]o after transient extracellular Ca2+ removal (32) was used to evaluate the role of SOCE. Figure 3, A and B, shows representative Ca2+ transient traces measured during fast switching from 0 to 2 mM [Ca2+]o for 3d and 56d myocytes, respectively. These data were collected in the presence of 10 µM NIF and 5 µM KB-R, both with and without SR Ca2+ depletion. SR Ca2+ depletion was achieved by continuous stimulation of the cell with depolarization (from –80 mV to +10 mV for 400 ms every 5 s) in the presence of 25 µM cyclopiazonic acid (CPA), a blocker of the SR Ca2+ pump, and 10 µM ryanodine (Ry), which locks the Ry receptor (RyR) in a subconducting open state. CAF (10 mM) was applied rapidly to verify that SR Ca2+ depletion was complete (see Supplemental Fig. 1; http://ajpcell.physiology.org/cgi/content/full/00226.2005/DC1). SOCE was then induced by a 10-s perfusion of 0 mM [Ca2+]o solution, followed by readdition of 2 mM [Ca2+]. This caused a substantial increase in [Ca2+]i in the 3d myocyte (Fig. 3A) but a significantly smaller increase in the 56d myocyte (Fig. 3B). [Ca2+]i reached a steady state within 100 s of switching solutions. It is important to note that an increase in [Ca2+]i was not observed when the SR was fully loaded with Ca2+, which is clearly shown in Fig. 3, A–C.
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F/F0) after [Ca2+]o was switched from 0 to 2 mM in control solution, 30 µM KB-R, or 100 µM SKF. The magnitude of the rise in [Ca2+]i in the presence of KB-R and SKF was significantly different from that observed under control conditions. Neither LOE-908 nor 2-APB had a significant effect on [Ca2+]i compared with the control group (data not shown).
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20 nm for both 3d and 56d myocytes. The SSC in the 56d myocytes form a tubulelike appearance as documented previously for a variety of adult mammalian species. The SSC in the 3d myocytes appeared to form sheetlike structures that extended along the apposing SL and were determined to be, on average, about three times longer than those in the 56d myocytes.
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DISCUSSION |
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SOCE in cardiac myocytes. The notion that the depletion of SR or ER could initiate the activation of plasma membrane Ca2+ entry through SOCs was first proposed in smooth muscles more than two decades ago, and the time of activation has been investigated in a variety of nonexcitable (7) and excitable cells, including smooth muscle (7, 8, 30, 42) and skeletal muscle cells (23). Another type of plasma membrane Ca2+ entry appears to be selective predominantly for Na+ over Ca2+ via the NSCC. Ca2+ influx through most SOCs can be blocked by the divalent cations Zn2+, Cd2+, Mn2+, Ni2+, and Ba2+ and by the trivalent cations La3+ and Gd3+ (2). Although it could be argued that Zn2+ may have some effect on Na+ and K+ channels, the presence of Zn2+ under our experimental conditions (–80 mV and K+ replacement) is unlikely to introduce any confounding consequences. Unfortunately, the lack of highly specific pharmacological tools has considerably impaired the identification of SOCs. SKF and 2-APB have been demonstrated as putative blockers of SOCE. LOE-908 has been implicated as an inhibitor of Ca2+-permeable NSCCs, but it did not inhibit SOCE in our present experiments.
In the current study, the two basic experimental protocols based on SR Ca2+ reloading after CAF exposure and readdition of Ca2+ after exposure to Ca2+-free extracellular solution both provided strong support for a robust SOCE in resting neonatal cardiac myocytes. Furthermore, significant inhibition of loadSR during the 60-s interval by both Zn2+ and SKF (Fig. 4), as well as the significant reduction of [Ca2+]i caused by SKF (Fig. 5A) but insensitivity to LOE-908, provides strong support for SOCE rather than nonspecific Ca2+ entry.
The interpretation of the effects of 2-APB is more complex. It has been known for some time that 2-APB is an inhibitor of inositol 1,4,5-trisphosphate (IP3) receptors (IP3Rs) (25) and at doses of 50–100 µM, 2-APB has been exploited to examine the role of IP3-mediated SOCE. However, 2-APB within the same concentration range also has been reported to inhibit a variety of transient receptor potential (TRP) channels, including subclasses of TRP melastatin (TRPM) channels and TRP vanilloid-related (TRPV) channels, some of which are purported to be responsible for SOCE (5, 6, 20, 37). Furthermore, higher doses of 2-APB increased Ca2+ influx in rat basophilic leukemia (RBL)-2H3 mast cells (
100 µM) (6) and heterologously expressed TRPV1–TRPV3 channels (>200 µM) (16). In the present study, we found that there were no significant differences in loadSR between 0, 50, 75, and 150 µM 2-APB (see Supplemental Fig. 2). Therefore, although the data in this study clearly support SOCE in the regulation of loadSR, the evidence for a role of IP3 in SOCE in cardiomyocytes is equivocal and requires further experimentation.
It has been reported that changes in intracellular [Mg2+] ([Mg2+]i) have an inhibitory effect on SOCE mediated by certain TRPCs (12, 38) by the binding of Mg2+ to the channel pore. However, extracellular [Mg2+]o has not yet been shown to have an effect on SOCs. For example, Warnat et al. (39) found that a change of [Mg2+]o from 0 to 2 mM had no effect SOCE in TRP4 channels expressed in Chinese hamster ovary (CHO) cells. In the present study, the substitution of [Ca2+]o with [Mg2+]o from 1 to 3 mM was consistently applied in all age groups for a short time (10 s) to improve seal stability. Therefore, the transient increase of [Mg2+]o is not likely to have an effect on the interpretation of our conclusions.
Role of NCX in SOCE in cardiac myocytes. Theoretically, the SOCE observed upon readdition of Ca2+ after exposure to Ca2+-free extracellular solution could result from reverse mode NCX if the NCX reversal potential (ENCX) at 2 mM [Ca2+]o and 150 nM [Ca2+]i in 3d myocytes (17) becomes more negative than –80 mV. This in turn would require that the subsarcolemmal [Na+] ([Na+]s) exceed 18 mM during prolonged perfusion with 0 mM [Ca2+]o (see Supplemental Table 1). We used two different approaches to limit [Na+]s accumulation. First, SR Ca2+ depletion was achieved by perfusing the cell with 25 µM CPA, 10 µM Ry, and 2 mM [Ca2+]o instead of pretreatment with 0 mM [Ca2+]o, because the time needed to reach SR Ca2+ depletion in this manner may result in [Na+]s >18 mM. Second, a 10-s perfusion time of 0 mM [Ca2+]o (Figs. 3 and 5) resulted in a change of [Ca2+]i that was <10% of the observed [Ca2+]i after switching to 2 mM [Ca2+]o. We submit, therefore, that the [Ca2+]i rise after switching [Ca2+]o from 0 to 2 mM in the present study was a consequence of SOCE only (Figs. 3 and 5).
In addition, loadSR was [Na+]o and [Na+]i dependent (Fig. 6A), which is explained by the resultant changes in ENCX (estimated to be –40, –50 and –77 mV for 140/10, 125/10, and 125/14 mV combinations, respectively; see Supplemental Table 1), and this dependence was abolished by 30 µM KB-R (Fig. 6B). One might argue that this slight modification of [Na+]o and [Na+]i might have an effect on either the Na+/K+ pump or Na+/H+ exchanger (NHE), which could have altered intracellular Ca2+ homeostasis in our experiments. However, experiments performed at the laboratories of Bers and Vaughn-Jones (4, 41) showed that variations in [Na+]i from 7 to 16 mm have little or no effect on NHE. Furthermore, both loadSR (Fig. 2A) and elevation of [Ca2+]i (Fig. 3A) under resting conditions were not blocked by 5 µM KB-R, a dose that effectively inhibited reverse mode NCX (see Supplemental Fig. 3), but instead were significantly increased in the presence of 30 µM KB-R, a dose reported to inhibit both reverse and forward mode NCX (1, 40) (Figs. 4 and 5, B and C), with the caveat that 30 µM KB-R is a relatively high dose. Therefore, this evidence strongly supports the notion that forward mode NCX efficiently competes with the SR Ca2+ pump for Ca2+ entering through SOC and agrees with a study by Chernaya et al. (9), who used transfected CHO cells that expressed bovine cardiac NCX. The present study was conducted at room temperature to preserve myocyte function and to prevent potential temperature gradients created by the rapid application of various solutions. This nonphysiological temperature results in an attenuation of both sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) and NCX activities. However, we think that our conclusions would remain qualitatively the same, although there might be quantitative differences, if the experiments had been conducted at physiological temperatures (37°C).
However, such a predominant role of forward mode NCX in limiting SOCE-dependent loadSR is contrary to observations in smooth muscle, neuronal, and nonexcitable cells, in which SR/ER Ca2+ refilling occurs primarily by reverse mode NCX activity (24). The reasons for this difference are not clear but may be related to different underlying mechanisms of SOCE. In particular, the selectivity of Ca2+ over Na+ and the fact that the activity of NCX in cardiac myocytes is more than 10-fold greater than that in smooth muscle (35), combined with the much slower kinetics of smooth muscle contraction, could critically alter the role of NCX in SOCE-dependent SR refilling.
Voltage dependence of SOCE. Assuming that the contribution of the sarcolemmal Ca2+ pump is minimal, the magnitude of loadSR appears to depend on competition between the SR Ca2+ pump and forward mode NCX for the SOCE. Thus more negative voltages increase the driving force for both SOCE (Fig. 5B) and forward mode NCX (Fig. 7). At a holding potential of –50 mV, the greater loadSR appears to be the consequence of Ca2+ entry by reverse mode NCX and/or L-type ICa, because it is dramatically reduced by the presence of 10 µM NIF and 5 µM KB-R. LoadSR exhibited linear voltage dependence on Em in the presence of 30 µM KB-R, consistent with an increased driving force for SOCE at more negative Em values and with the fact that SOCs are not voltage-gated channels. Therefore, loadSR in the presence of 30 µM KB-R is more likely to reflect the actual SOCE, which is about twofold greater than that observed without KB-R.
Developmental changes in SOCE.
Both the rise in [Ca2+]i when [Ca2+]o was switched from 0 to 2 mM (Fig. 3) and the loadSR observed during resting conditions (Fig. 1) were significantly greater in 3d than in 56d myocytes, even though the 60-s loadSR was only 50% of the steady-state loadSR in 3d myocytes (61.9 amol/pF) (17). In the present study, loadSR after the 10-s interval was 10 and 2 amol/pF in 3d and 56d myocytes, respectively, producing average SOC currents of 0.2 and 0.04 pA/pF, respectively, assuming that SOC exhibits high Ca2+ selectivity that is too small to be detected using the whole cell voltage patch-clamp technique. These values are considerably lower than the SOC density of 0.7 pA/pF at –90 mV in rat cardiomyocytes reported recently by Hunton and colleagues (19, 20). It should be taken into consideration that SOC density of 0.7 pA/pF is similar to the peak INCX density elicited by 10 mM CAF in the rat and that it would load the adult rat SR at rest within 20–30 s. This suggests that the reported SOC density of 0.7 pA/pF is likely overestimated, possibly because of prolonged exposure to Ca2+-free extracellular solution and the use of Ca2+ chelators and ionophores. Furthermore, the likelihood of higher surface-to-volume ratios in the younger age groups could yield appreciable [Ca2+]i changes as well as the underestimation of loadSR normalized by cell membrane surface (pF) (14). Therefore, although the increased [Ca2+]i (Fig. 3) might be overestimated, it would not change the conclusion of developmental change in SOCE due to the strong support from the developmental change in loadSR.
Close spatial relationships between SOC, NCX, and SERCA2A within a microdomain are unique to neonatal myocytes.
In the absence of SR Ca2+ pump inhibition during the 60-s period of loadSR (Figs. 1B and 2A), there was no detectable increase in Ca2+ fluorescence (Fig. 3). Therefore, it is likely that Ca2+ influx into a microdomain between the sarcolemma and the SR through the SOCs is pumped back to the SR by SERCA before it reaches the bulk phase cytosol (29). As predicted, blockade of SERCA with CPA revealed SOCE as a rise in [Ca2+]i. The efficiency of transfer of Ca2+ from SOCE to SERCA depends on the spatial relationship between SERCA and SOC and the kinetics of SR Ca2+ uptake and SOCE. SOCE has an overall lower rate compared with SR Ca2+ uptake rate (11), presumably as a consequence of their relative densities (15). Thus little or no increase in [Ca2+]i would be expected if SOCs were in proximity to the SR Ca2+ pump. Page and Buecker (28) found that before the development of a T-system (10 days after birth), the surface density of dyads as well as total dyad areas per unit of cell volume and per unit of myofibrillar volume increase progressively during embryogenesis until they approach constancy at near-adult rabbit values 1 day after birth. Furthermore, in the present study, we have presented the novel finding of the abundant sheetlike SSCs in 3d myocytes in contrast to tubular SSCs in 56d myocytes. This finding, as well as the narrow cleft (20 nm) between SL and SR (Fig. 8), provides strong structural support for the existence of a distinct SL microdomain and thus the functional link between SOC, SERCA2A, and NCX in neonatal cardiomyocytes. The functional studies conducted at our and other laboratories have shown that there is a much greater SR Ca2+ content than previously recognized and that reverse mode NCX plays a more important role in excitation-contraction (E-C) coupling in the early developmental stages (17, 18). Furthermore, we have demonstrated a significantly greater time delay between the peaks of INCX and Ca2+ transient induced by rapid CAF application in myocytes from the youngest age groups (287 ms in 3d vs. 64 ms in 20d), as well as a significantly greater amount of Ca2+ already pumped out at the time of peak Ca2+ transient (50% of total Ca2+ in 3d vs. 17% of total Ca2+ in 20d) (17). These results support the hypothesis that there are ultrastructural differences in the subsarcolemma SR microdomain (17, 34) as a function of ontogeny. We propose, therefore, that NCX, SOC, and SERCA are in proximity to each other in the 3d myocyte as reported with regard to mature smooth muscle (27). We postulate that the depletion of SR Ca2+ in neonatal ventricular myocytes triggers SOCs, which brings Ca2+ into a restricted microdomain between the SL and peripheral SR membrane in the neonatal heart. Because NCX has a substantive impact on SOCE-dependent loadSR, it must be close enough to the SOC to be able to compete effectively with SERCA for SOCE. In addition, both NCX and SERCA might contribute to normal heart function by preventing an increase in [Ca2+]i during SR Ca2+ refilling. Further examination of the proximity of the proteins proposed in this model is required.
Mechanism and function of SOCE. Because it has commonly been accepted that SOCE does not exist in cardiomyocytes, the mechanism and function of SOCE in heart was not investigated until Hunton et al. (19) suggested that SOC might be involved in Ca2+-mediated hypertrophy in rat cardiomyocytes. The present study is the first report of developmental regulation of SOCE, and these findings may be consistent with the observations of the latter study in that this period of ontogeny is characterized by substantial cardiomyocyte hypertrophic growth. In our study, myocyte surface area increased by >470% during the 3d–56d period on the basis of measurement of membrane capacitance (14.2 ± 0.5 vs. 68.0 ± 0.9 pF, respectively).
As a result of the apparently low unitary conductance and density of SOC, SOCE is unlikely to make a significant contribution to E-C coupling even in the neonatal myocyte. Thus the SOCE-dependent loadSR of 10 amol·pF–1·10 s–1 in the 3d myocyte corresponds to an uptake rate of 6.4 µM/s (assuming a conversion factor of 6.44 pF/pl), which is 10% of the total Ca2+ transient. However, the data suggest that SOCE is likely to play an important role in maintaining SR Ca2+ homeostasis, especially in the neonatal heart.
In conclusion, our results show that in the newborn rabbit, there is a robust reloading of SR Ca2+ (after CAF-induced clearance of SR Ca2+ content) mediated by SOCE and strongly modulated by NCX activity, suggesting that SOC, SERCA2A, and NCX are colocalized within a subsarcolemmal microdomain. Although the SOCE-dependent loadSR is estimated to be too slow to contribute significantly to cytosolic Ca2+ cycling on a beat-to-beat basis, SOCE-dependent loadSR, together with NCX, may play an important role in SR Ca2+ homeostasis in the neonatal heart. This orchestrated interplay between SOCE, NCX, and SERCA2A may be of particular importance during open heart surgery in the neonate, in which an alteration of this balance could lead to uncontrolled SOCE-dependent loadSR and arrhythmogenesis.
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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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REFERENCES |
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P < 0.001, respectively) and for the 60-s interval between 140/10 vs. 125/14 mM (*P < 0.05). No significant differences were observed regarding the 10-s interval between 125/10 and 140/10 mM or regarding the 60-s interval between 125/10 vs. 125/14 mM and 140/10 mM. n = 15. B: 10-s loadSR was significantly increased in the presence of 30 µM KB-R (solid bars) in both 125/10 and 140/10 mM groups compared with control groups (gray bars). 
