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Cardiovascular |
1 Department of Physiology, Loyola University Chicago, Maywood, IL 60153, USA
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Abstract |
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(Received 8 December 2005;
accepted after revision 12 February 2006;
first published online 16 February 2006)
Corresponding author L. A. Blatter: Department of Physiology, Loyola University Chicago, 2160 S. First Avenue, Maywood, IL 60153, USA. Email: lblatte{at}lumc.edu
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Introduction |
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In contrast to ventricular myocytes, in other cardiac cell types, such as neonatal myocytes, pacemaker cells, atrial myocytes or Purkinje cells the t-tubular system is poorly developed or entirely absent (Huser et al. 1996). In cells lacking t-tubules, two types of SR can be defined, based on their location relative to the surface membrane. Junctional SR (j-SR) is found in the cell periphery, where it is organized in peripheral couplings, i.e. the SR membrane is found in close spatial association with the surface membrane, similar to the diadic cleft in ventricular myocytes (McNutt & Fawcett, 1969; Kockskamper et al. 2001). In contrast, non-junctional SR (nj-SR) is found in deeper regions of the cell and does not associate with the surface membrane. Both j-SR and nj-SR possess RyRs (Carl et al. 1995; Kockskamper et al. 2001; Mackenzie et al. 2001) and have been shown to be capable of active SR Ca2+ release. Nonetheless, the detailed mechanisms that regulate Ca2+ release from nj-SR are still poorly understood, and its relevance to excitation–contraction coupling (ECC) has remained controversial (e.g. Blatter et al. 2003).
Cells lacking t-tubules also show variable spontaneous Ca2+ spark activity. In neonatal cells, where the t-tubular system is still developing, Ca2+ sparks are restricted to the cell periphery and are associated with caveolae (Lohn et al. 2000). In rabbit Purkinje cells, which also lack t-tubules but contain peripheral and central RyRs (Cordeiro et al. 2001), Ca2+ sparks occur only at the cell periphery, even during ß-adrenergic stimulation. In contrast, in canine Purkinje cells, Ca2+ sparks occur ubiquitously throughout the cell (Stuyvers et al. 2005). In rat atrial cells, Ca2+ sparks have been observed in the central and subsarcolemmal regions of the myocytes with no significant differences in frequency, amplitude or kinetics (Tanaka et al. 2001). This is in contrast to the finding of ‘eager’ Ca2+ release sites in the periphery of rat atrial myocytes with a high propensity for spontaneous Ca2+ sparks (Mackenzie et al. 2001) and the observation that the vast majority of Ca2+ sparks are associated with sarcolemmal membranes or the irregular internal transverse-axial tubular system (TATS) found in rat atrial cells (Kirk et al. 2003). Furthermore, aside from different frequencies, peripheral and central Ca2+ sparks in rat atrial myocytes have also been found to have differing spatiotemporal characteristics (Woo et al. 2003a), and it has been suggested that the higher frequency of peripheral Ca2+ sparks may result from interactions between the 
1C subunit of the DHPR with the RyR (Woo et al. 2003b).
We showed previously (Huser et al. 1996) that in cat atrial myocytes (which completely lack t-tubules) Ca2+ sparks originate from both j-SR and nj-SR, but that spontaneous Ca2+ sparks from j-SR occur at a significantly higher frequency than nj-SR Ca2+ sparks, despite the observation that both the j-SR and nj-SR contain RyR clusters with comparable density and spatial organization (Kockskamper et al. 2001). Thus, the goal of the present study was to determine whether the lower spontaneous Ca2+ spark activity from nj-SR resulted from an intrinsic difference in the Ca2+ release machinery or in the Ca2+ load between j-SR and nj-SR in cat atrial myocytes. A preliminary account of this work has appeared in abstract form (Sheehan & Blatter, 2002).
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Methods |
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Single myocytes were isolated from cat atria as previously described (Wu et al. 1991; Kockskamper & Blatter, 2002; Sheehan & Blatter, 2003). The procedure for cell isolation was fully approved by the Institutional Animal Care and Use Committee of Loyola University Medical Center. Thirty-four hearts were used to isolate atrial myocytes. Briefly, adult mongrel cats of either sex were anaesthetized with thiopentone sodium (35 mg kg–1I.P.). Following thoracotomy, hearts were quickly excised, mounted on a Langendorff apparatus, and retrogradely perfused with oxygenated collagenase-containing solution at 37°C. Cells were plated onto coverslips for later experimentation. All experiments were carried out at room temperature (22–25°C).
Measurements of intracellular calcium
Intracellular calcium ([Ca2+]i) was measured in intact and permeabilized atrial myocytes with fluorescence laser scanning confocal microscopy. Intact atrial myocytes were loaded with the Ca2+ indicator fluo-4 by 20 min incubation in Tyrode solution containing 20 µM fluo-4 AM (fluo-4 acetoxymethyl ester; Invitrogen/Molecular Probes, Carlsbad, CA, USA) at room temperature. A glass coverslip with the cells was mounted in an experimental chamber on the stage of an inverted microscope. Cells were superfused continuously (1 ml min–1) with normal Tyrode solution (composition, mM: NaCl, 140; KCl, 4; CaCl2, 2; MgCl2, 1; glucose, 10; and Hepes, 10; pH adjusted to 7.4 with NaOH). Fifteen to twenty minutes were allowed for de-esterification of the dye. Measurements of [Ca2+]i were performed with laser scanning confocal microscopy (LSM 410; Carl Zeiss, Oberkochen, Germany; and Radiance 2000 MP, Hertfordshire, Bio-Rad, UK). Fluo-4 was excited with the 488 nm line of an argon ion laser, and fluorescence was measured at wavelengths > 515 nm. Images were acquired in the linescan mode (1.4–3.0 ms per scan; pixel size of 0.1 µm). All linescan images were recorded by placing the scanning line parallel to the longitudinal axis of the cell at a central focal plane.
For experiments in permeabilized cells, the surface membrane was permeabilized by exposure to 0.005% (w/v) saponin (Zima et al. 2003). After 30 s the bath solution was exchanged to a saponin-free internal solution composed of (mM): potassium aspartate, 100; KCl, 15; KH2PO4, 5; MgATP, 5; EGTA, 0.4; CaCl2, 0.12; MgCl2, 0.75; phosphocreatine, 10; creatine phosphokinase, 5 U ml–1; dextran (MW 40 000 Da), 8%; Hepes, 10; and fluo-4 potassium salt, 0.03; pH adjusted to 7.2 with KOH. The free [Ca2+] and [Mg2+] of this solution were 100 nM and 1 mM, respectively (calculated using WinMAXC 2.05, Stanford University, CA, USA).
Calcium spark frequencies and characteristics were determined from linescan images using an automated spark detection and quantification algorithm (Cheng et al. 1999; Zima et al. 2004). Calcium sparks were quantified in terms of amplitude (F/F0), full-width at half-maximum amplitude (FWHM, in µm), and duration at half-maximum amplitude (in ms). F0 is the fluoresecence (F) recorded under steady-state conditions at the beginning of an experiment. Calcium spark frequencies are expressed as number of observed sparks per second and per 100 µm of scanned distance (sparks s–1 (100 µm)–1). Prior to the recording of Ca2+ sparks in resting intact myocytes, cells were field-stimulated to elicit action potentials (APs) and to establish uniform SR Ca2+ loading conditions.
Data analysis
Results are reported as means ±S.E.M. for the indicated number (N) of cells or number (n) of Ca2+ sparks. Statistical significance was evaluated using Student's t test.
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Results |
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We systematically compared the properties of Ca2+ sparks recorded from the subsarcolemmal (SS) j-SR and central(CRT) nj-SR of intact atrial myocytes under control conditions ([Ca2+]o, 2 mM; [Na+]o, 140 mM). Figure 1A shows linescan images of SS and CTR Ca2+ sparks recorded from the same cell. To record SS Ca2+ sparks the scan line was positioned within less than 1 µm from the edge of the cell and orientated parallel to the longitudinal cell axis. In the axial dimension, the focal plane was set at the central depth of the cell, i.e. at an equal distance from the lower and upper cell border. The traces beneath the linescan images represent local changes of [Ca2+]i (F/F0, averaged over a distance of 1 µm) recorded from selected subcellular regions marked by the black squares to the left of the images. As summarized in Table 1, the most striking difference between spontaneous SS and CTR Ca2+ sparks was their frequency of occurrence. Subsarcolemmal Ca2+ sparks were 3–4 times more frequent than CTR sparks (6.6 ± 1.5 versus 1.9 ± 0.5 sparks s–1 (100 µm)–1; N= 14 cells; P < 0.005; unpaired t test). The amplitude (F/F0) of CTR Ca2+ sparks was on average about 10% lower compared to SS Ca2+ sparks, whereas spatial width and duration were essentially identical in both regions.
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Effect of sensitization of RyR to cytosolic Ca2+
We explored whether increasing the sensitivity of the RyR to Ca2+ could activate ‘silent’ RyR clusters in the nj-SR membrane in intact myocytes. For this purpose we used caffeine at a low concentration (0.1 mM), which does not evoke global SR Ca2+ release but substantially sensitizes RyRs to cytosolic Ca2+ and to Ca2+-induced Ca2+ release. As shown in Fig. 1B, in the presence of caffeine, the frequency of both SS and CTR Ca2+ sparks increased substantially. In this set of experiments (N= 5) Ca2+ spark frequency was measured in the same cells, first under control conditions, followed by exposure to 100 µM caffeine. The average Ca2+ spark frequency increased from 4.1 ± 0.6 to 5.7 ± 0.7 sparks s–1 (100 µm)–1 in the SS region, whereas in the CTR region the frequency increased from 1.6 ± 0.3 to 3.0 ± 0.3 sparks s–1 (100 µm)–1 (Fig. 1C). Even though the overall absolute SS Ca2+ spark frequency remained higher in the SS space, the relative effect on the nj-SR was significantly more pronounced (Fig. 1D). Within 2 min after addition of caffeine, Ca2+ spark frequency increased on average by only 58 ± 11% (N= 5; P < 0.01) in the SS region of cells, whereas in the cell centre the frequency increased by 107 ± 22% (N= 5; P < 0.05). These data indicate that increasing the sensitivity of RyRs to Ca2+ makes the regional differences in Ca2+ spark activity (j-SR versus nj-SR) significantly less pronounced.
Role of extracellular Ca2+ and Ca2+ influx for Ca2+ spark activation
A key feature of the ultrastructural organization of the j-SR is the close apposition of surface membrane L-type Ca2+ channels (DHPRs) and RyRs in the j-SR membrane (Kockskamper et al. 2001). This arrangement suggests that stochastic openings of DHPRs and the subsequent Ca2+ entry would expose j-SR RyRs to high activating [Ca2+]i more frequently than nj-SR RyRs and therefore could be responsible for the higher propensity of peripheral SS Ca2+ sparks. The following experiments were aimed to determine the role of Ca2+ entry from the extracellular space in Ca2+ spark activation in atrial cells.
In order to investigate the role of Ca2+ entry through L-type Ca2+ channels in spontaneous Ca2+ spark activation originating from the j-SR and nj-SR of intact atrial myocytes, we used the DHPR inhibitor verapamil (20 µM). Figure 2A shows confocal linescan images of Ca2+ sparks and plots of F/F0 from different subcellular regions under control conditions and after addition of verapamil. As illustrated in Fig. 2A, Ca2+ sparks that originated from the SS region were significantly more sensitive to verapamil treatment than CTR Ca2+ sparks. On average (Fig. 2B), the frequency of SS Ca2+ sparks was reduced by nearly two-thirds to 38 ± 7% of control values (N= 5 cells; P < 0.05), whereas the frequency of CTR Ca2+ sparks decreased by less than 20% (81 ± 11% of control values; N= 5; n.s.). The data suggest that spontaneous openings of L-type Ca2+ channels determine the Ca2+ spark activity from j-SR, but had little influence on the frequency of Ca2+ sparks from nj-SR.
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Sarcoplasmic reticulum Ca2+ content is known to influence the frequency and amplitude of Ca2+ sparks (e.g. Satoh et al. 1997; Zima et al. 2004). To determine whether the differences and changes in SS and CTR Ca2+ spark activity in 2Ca/140Na and 0Ca/0Na resulted from differences in Ca2+ load (and changes of it) of the j-SR and the nj-SR, we measured local SR Ca2+ load by challenging intact cells with 10 mM caffeine. For these experiments, the scan line was orientated perpendicular to the longitudinal axis of the cell (transverse linescan), which allowed simultaneous visualization of [Ca2+]i in the SS and CTR regions. There was no statistically significant difference in caffeine-releasable SR Ca2+ between these two regions when the cells were rested in 2Ca/140Na. The amplitude (F/F0) of the caffeine-induced [Ca2+]i transient was 9.2 ± 1.9 in the SS space and 8.9 ± 1.9 in the CTR region (N= 10 cells). In 0Ca/0Na, the regional SR load was overall slightly (but not significantly) higher. In 0Ca/0Na, the amplitude of the SS caffeine-induced Ca2+ signal was F/F0= 10.3 ± 1.2, which was about 10% higher than CTR Ca2+ load (F/F0= 9.2 ± 1.0; N= 14 cells; n.s.). These results indicate that adequate SR Ca2+ was available for release under all experimental conditions, and the significant differences in Ca2+ spark frequency from the j-SR and nj-SR cannot be explained by large regional differences in SR Ca2+ load.
Characteristics of Ca2+ sparks in permeabilized cat atrial myocytes
To eliminate the influence of Ca2+ influx on spontaneous Ca2+ sparks and to gain control of [Ca2+]i surrounding RyRs of both the j-SR and nj-SR we studied Ca2+ sparks in saponin-permeabilized atrial myocytes. This technique allows control of the cytoplasmic milieu regarding its ionic composition (including [Ca2+]), while maintaining the SR structurally and functionally intact (Zima et al. 2003). Figure 4A shows representative confocal linescan images of Ca2+ sparks and plots of F/F0 from SS and CTR regions of an atrial cell after permeabilization of the sarcolemma (free [Ca2+]i, 100 nM). In permeabilized myocytes, the differences between SS and CTR Ca2+ spark frequencies and spatiotemporal characteristics (Table 2) were completely eliminated. On average, the frequencies of SS and CTR Ca2+ sparks were not statistical different, and amounted to 8.5 ± 1.3 and 9.6 ± 0.4 sparks s–1 (100 µm)–1, respectively (N= 10 cells). Figure 4B shows Ca2+ spark sites in SS and CTR regions at higher magnification. It is evident that essentially all j-SR and nj-SR Ca2+ release units show Ca2+ spark activity (arrowheads in Fig. 4B). Calcium spark locations were found at regular spatial distances with an average spacing of 
1.8–2.0 µm, i.e. in an identical spatial pattern that corresponds to the previously determined distribution of RyRs in cat atrial myocytes (Kockskamper et al. 2001). During high Ca2+ spark activity, multifocal Ca2+ sparks (or propagating sparks) spanning over several neighbouring release sites could be observed (Fig. 4B). The data suggest that, under identical activation conditions ([Ca2+]i), spontaneous j-SR and nj-SR Ca2+ sparks are not different in their unitary characteristics and occur at the same frequency. Thus, in cat atrial myocytes, nj-SR RyRs are fully capable of robust Ca2+ release and, in intact cells, the primary difference between spontaneous Ca2+ sparks from the j-SR versus nj-SR is the trigger mechanism. Our data suggest that the DHPR plays a key role in this process and that the close apposition of DHPR and RyRs in the peripheral couplings of the j-SR, together with spontaneous openings of the DHPRs allowing Ca2+ influx, is a key factor for the higher frequency of Ca2+ sparks in the SS space.
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Discussion |
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While many aspects regarding the mechanisms that control central Ca2+ release remain poorly understood, it becomes increasingly clear that nj-SR is fully equipped for robust Ca2+ release; however, the efficacy of Ca2+ release under physiological conditions is relatively low. This allows for a high dynamic range for regulation and adaptation of central Ca2+ release. Central Ca2+ release is responsive to positive inotropic stimuli (Mackenzie et al. 2004a; Li et al. 2005). The unique mechanism underlying the positive inotropic reserve in atrial myocytes consists of an increase of the efficacy of nj-SR Ca2+ release, possibly through recruitment of normally silent RyRs (Mackenzie et al. 2004a), whereas in ventricular myocytes positive inotropic agents act through enhancing Ca2+ release from already active release sites. While atrial contractions contribute relatively little to ventricular filling (preload) and ultimately cardiac output at rest, their contributions and haemodynamic consequences under specific physiological and pathophysiological conditions (Naito et al. 1983; Nishimura et al. 1995; Tada et al. 2002) have been recognized clinically for a long time (Braunwald & Frahm, 1961). For example, sympathetic stimulation during exercise significantly increases atrial contraction and contribution to ventricular filling. Atrial filling fraction increases with age (Kuo et al. 1987) and, in cardiac hypertrophy, where ventricular compliance is reduced, atrial contraction contributes significantly to ventricular filling and cardiac output even at rest. Consequently, loss of effective atrial contraction prevents patients with atrial fibrillation from performing strenuous exercise, impairs ventricular function (Yu et al. 2001), and can lead (together with an irregular and increased ventricular heart rate) to an acute decompensation of an otherwise compensated cardiac disease (Nattel, 2002).
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Footnotes |
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Acknowledgements |
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Author's present address
K. A. Sheehan: Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL 60612, USA.
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