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Departments of 1 Anesthesiology and of 4 Physiology and Biophysics, Mayo Foundation, Rochester 55905; and Departments of 2 Veterinary Pathobiology and 3 Pharmacology, University of Minnesota, St. Paul, Minnesota 55108
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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cADP ribose (cADPR)-induced intracellular Ca2+ concentration ([Ca2+]i) responses were assessed in acutely dissociated adult rat ventricular myocytes using real-time confocal microscopy. In quiescent single myocytes, injection of cADPR (0.1-10 µM) induced sustained, concentration-dependent [Ca2+]i responses ranging from 50 to 500 nM, which were completely inhibited by 20 µM 8-amino-cADPR, a specific blocker of the cADPR receptor. In myocytes displaying spontaneous [Ca2+]i waves, increasing concentrations of cADPR increased wave frequency up to ~250% of control. In electrically paced myocytes (0.5 Hz, 5-ms duration), cADPR increased the amplitude of [Ca2+]i transients in a concentration-dependent fashion, up to 150% of control. Administration of 8-amino-cADPR inhibited both spontaneous waves as well as [Ca2+]i responses to electrical stimulation, even in the absence of exogenous cADPR. However, subsequent [Ca2+]i responses to 5 mM caffeine were only partially inhibited by 8-amino-cADPR. In contrast, even under conditions where ryanodine receptor (RyR) channels were blocked with ryanodine, high cADPR concentrations still induced an [Ca2+]i response. These results indicate that in cardiac myocytes, cADPR induces Ca2+ release from the sarcoplasmic reticulum through both RyR channels and via mechanisms independent of RyR channels.
heart; ryanodine receptor; second messenger; confocal microscopy; sarcoplasmic reticulum; intracellular calcium concentration
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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STUDIES IN A VARIETY OF
TISSUES have shown that cyclic ADP ribose (cADPR), a metabolite
of 
-nicotinamide adenine dinucleotide (NAD), can induce
sarcoplasmic reticulum (SR) Ca2+ release (3, 6, 9,
12, 14, 16, 23), most likely through ryanodine receptor (RyR)
channels (3, 9, 10, 12, 14, 23). The cADPR-induced SR
Ca2+ release is inhibited by 8-amino-cADPR, a selective
cADPR receptor antagonist (18, 22). However, the response
to caffeine is unaffected, suggesting that cADPR does not directly
activate RyR channels. Indeed, high-affinity cADPR binding sites in the
SR membrane distinct from the RyR channel itself have been demonstrated (3, 9, 20).
Although the enzymes required for cADPR synthesis and degradation have been identified in cardiac muscle (13, 19) and endogenous levels have been estimated to be in the submicromolar range (21), the role of cADPR in cardiac muscle remains controversial. In canine cardiac microsomal preparations, micromolar concentrations of cADPR have been shown to induce Ca2+ release (8, 12). In contrast, in rat cardiac myocytes, some studies have reported that flash photolysis of caged cADPR does not induce SR Ca2+ release (4), whereas more recent studies have shown modulation of intracellular Ca2+ concentration ([Ca2+]i) by photolyzed cADPR (1, 17). Consistent with these latter studies, 8-amino-cADPR has been shown to inhibit Ca2+ transients in guinea pig cardiac myocytes (18).
The purpose of the present study was to determine whether cADPR affects the regulation of [Ca2+]i in the heart under various conditions of myocyte activation. Using the left ventricle of the adult rat, we examined the effects of exogenous (injected) cADPR on [Ca2+]i regulation in freshly dissociated single myocytes. We hypothesized that cADPR affects SR Ca2+ release through RyR channels and influences the sensitivity of Ca2+-induced Ca2+ release through these channels.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Cell preparation. All procedures involving animal use were reviewed and approved by the Institutional Animal Care and Use Committee of the Mayo Clinic.
Adult male Sprague-Dawley rats (250-300 g body wt) were anesthetized with ketamine (60 mg/kg) and xylazine (2.5 mg/kg) administered intramuscularly, and the heart, lungs, and descending aorta were quickly excised and immersed in oxygenated, ice-cold balanced salt solution (130 mM NaCl, 3 mM KCl, 1.2 mM KH2PO4, 1.0 mM MgSO4, 1.25 mM CaCl2, 10 mM HEPES, and 10 mM glucose; pH 7.20). The procedure for isolation of Ca2+-tolerant cardiac myocytes was essentially a Langendorff perfusion-based technique described by De Young et al. (2), which uses a Dulbecco's minimum essential medium (Joklik's modification; enriched with 10 mM KCl and 10 mM HEPES). The Ca2+ concentration in the dissociation medium varied depending on the dissociation step. The present study used a slight modification to the published procedure: the original procedure called for a final Ca2+ concentration of 2.5 mM, whereas we used 1 mM. The isolation procedure typically yielded
105 cells/ml,
with 50-60% viable and usable cells (see below). Isolated
myocytes were plated at a low density (10-25
cells/mm2) on laminin-coated glass coverslips. Cells were
used for experiments within 2-3 h following plating. The viability
and Ca2+ tolerance of the isolated cells were indexed by
the presence of uniformly spaced sarcomeres, stable, low basal
[Ca2+]i level, infrequent, spontaneous
contractions (and accompanying [Ca2+]i
waves), contractile response to electrical stimulation, and the absence
of blebs on cell surfaces.
Measurement of [Ca2+]i. Dissociated cardiac myocytes attached to laminin-coated coverslips were incubated in 5 µM of the acetoxymethyl ester of fluo-3 (fluo-3/AM; Molecular Probes, Eugene, OR) at 37°C for 30 min, and then placed on an open slide chamber (Warner Instruments, Hamden, CT) mounted on a Nikon Diaphot inverted microscope. The chamber was perfused with Ca2+-Joklik's containing 1 mM Ca2+ at 2-3 ml/min at room temperature.
Fluo-3-loaded cells were visualized using an Odyssey XL real-time confocal system (Noran Instruments, Middleton, WI) attached to the Nikon microscope and equipped with an Ar-Kr laser. In previous studies (e.g., Ref. 15), we have used real-time confocal imaging to examine both spatial and temporal aspects of [Ca2+]i dynamics. However, in the present study, the system was used predominantly to examine temporal aspects, within small regions of a myocyte. Although the confocal system was capable of acquiring images at 480 frames/s, in preliminary studies, we determined that 30 frames/s was sufficient to determine the dynamic [Ca2+]i response of cardiac myocytes for the protocols in the present study, without introducing frequency aliasing. An Olympus ×40/1.3 oil-immersion objective lens was used for imaging with image size set to 640 × 480 pixels (0.06 µm2/pixel). Optical section thickness was set to 1 µm. With regions of interest (ROIs) of 5 × 5 pixels (1.5 µm2), [Ca2+]i measurements were obtained from volumes of 1.5 µm3.Ca2+ calibrations.
Since fluo-3 is a nonratiometric Ca2+ indicator,
differences in dye loading and photobleaching may affect the estimation
of [Ca2+]i based on fluorescence intensity.
Therefore, an empirical calibration curve of fluorescence intensity vs.
Ca2+ level was generated, as described previously
(15). Based on previous experience in other cell systems,
a fixed combination of laser intensity (20% of maximum) and
photomultiplier gain (1,700 from a maximum of 4,096) was set a priori
to ensure that pixel intensities within ROIs ranged between 25 and 255 gray levels (GL). In initial calibrations, no cells were used, and 5 µM of the pentapotassium form of fluo-3 (Molecular Probes) was added to a series of Ca2+ calibration buffers. Since this form of
fluo-3 directly fluoresces on binding to Ca2+, the
fluorescence intensities (in GL) could be directly mapped to
Ca2+ levels (in nM). In the next set of calibrations,
cardiac myocytes loaded with 5 µM fluo-3/AM were sequentially exposed
to solutions containing either 225 nM or 1.25 µM Ca2+,
and 10 µM of the Ca2+ ionophore A-23187, thus
equilibrating intra- and extracellular Ca2+ concentrations.
The calculated nanomolar Ca2+ based on GL data under these
conditions was not significantly different (
5 GL) from that
calculated using the acellular preparation.
[Ca2+]i response to cADPR.
Cardiac myocytes displaying stable basal
[Ca2+]i levels (i.e., no spontaneous
fluctuations in resting [Ca2+]i levels) were
located, brought into the imaging field, and impaled with single-lumen
glass micropipettes (1.5 mm OD; World Precision Instruments) that were
pulled to a fine tip using a Brown-Flaming electrode puller. The
electrode tip resistance was found to be <100 K
when filled with
100 µM cADPR concentrations in 1 mM LiCl. The average tip diameter
was estimated to be <5 µm. The cADPR solution was injected into the
myocyte using pressure injection (PicoSpritzer, General Valve) during
simultaneous monitoring of [Ca2+]i responses.
Since the final cADPR concentration in the cell following injection was
dependent on cell volume, the volumes of ~10 myocytes were estimated
a priori from online length and breadth measurements (~100,000
µm3). Based on this cell volume, the total time and
amplitude of the pressure pulse was then set such that the volume
injected resulted in a final intracellular concentration of one of four values (100 nM, 300 nM, 1 µM, and 3 µM).
Effect of 8-amino-cADPR. Myocytes displaying spontaneous waves were injected with 20 µM 8-amino-cADPR, a specific blocker of the cADPR binding site. The [Ca2+]i response to 8-amino-cADPR was then monitored. The myocytes were finally exposed to 5 mM caffeine.
In a separate set of experiments, electrically paced myocytes were injected with 20 µM 8-amino-cADPR, and the [Ca2+]i response was monitored. The myocytes were finally exposed to 5 mM caffeine.Effect of ryanodine. Quiescent myocytes (not paced) were exposed to 10 µM ryanodine, and the lack of an [Ca2+]i response to 5 mM caffeine was verified. The cells were then injected with different cADPR concentrations.
In a separate set of experiments, electrically paced cardiac myocytes were first exposed to 10 µM ryanodine for 10 min. The cells were then injected with different cADPR concentrations.Statistical analysis. A total of 15 animals were used for the present study. No protocol was performed on cells isolated only from a single animal. Each protocol was performed on cells isolated from at least four animals. At least 5 cells, but not more than 10 cells per animal, were used in any protocol. Accordingly, each protocol was performed on at least 20 cells (range 27-62 cells). The specific numbers of animals analyzed for each protocol are provided in RESULTS. Different parameters such as the amplitude of the [Ca2+]i response and frequency of [Ca2+]i waves (see RESULTS) were compared for the effects of cADPR using Student's t-tests, where each cell served as its own control. Concentration response curves were evaluated using ANOVA and repeated measures design (Bonferroni correction). Statistical significance was tested at a 0.05 level. Data are presented as means ± SE.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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[Ca2+]i response to cADPR.
In quiescent myocytes, basal [Ca2+]i ranged
from 90-140 nM (110 ± 21 nM; n = 15).
Injection of vehicle produced only a small and statistically
insignificant elevation in [Ca2+]i levels,
even for different volumes of injection (range 25-40 nM;
n = 6). Injection of cADPR (100 nM, 300 nM, 1 µM, and
3 µM) produced significant, stable concentration-dependent,
elevations in [Ca2+]i, with the effects being
maximum at 3 µM (Fig. 1;
P 0.05 for all concentrations, n = 9).
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0.05 for 1 and 3 µM, n = 7). However, there was a concomitant increase in the frequency of the waves (Fig. 2B;
P 0.05 for all concentrations except 100 nM). In
four cells (from two animals), injection of micromolar concentrations
of cADPR produced irregularities in the waves, making it difficult to
quantitatively evaluate the effect of cADPR on frequency. These cells
were excluded from further analysis. Injection of vehicle produced only
a temporary increase in wave frequency that lasted 5-10 s but did
not show any change in amplitude. This increase in frequency in vehicle
controls was significantly less than that induced even by 100 nM cADPR.
Furthermore, in these control experiments, repeated injections of
vehicle produced approximately the same increase in wave frequency upon
each injection (data not shown).
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0.05 for all
concentrations, n = 8). There was no obvious increase in the width of the [Ca2+]i response
(measured at half maximum; 0.57 ± 0.03 s prior to cADPR
exposure) with 100 nM or 300 nM cADPR (5 ± 2% and 8 ± 3% of control, respectively); however, both 1 and 3 µM cADPR prolonged the duration of the [Ca2+]i response to
stimulation by (14 ± 3% and 26 ± 4%, respectively; P 0.05 for each). Injection of vehicle increased the
amplitude of the [Ca2+]i response by 4 ± 2%.
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Effect of 8-amino-cADPR.
In myocytes displaying spontaneous [Ca2+]i
waves, injection of 20 µM 8-amino-cADPR, a specific blocker of the
cADPR binding site (18, 22), produced significant
reduction in the amplitude of the waves (14 ± 8% of control;
P 0.05, n = 7), completely inhibiting the waves in more than 50% of cells (e.g., Fig.
4A). However, even in the
continued presence of 8-amino-cADPR, 5 mM caffeine produced a transient
[Ca2+]i response that had an amplitude
88 ± 17% of the amplitude of the spontaneous waves prior to
8-amino-cADPR exposure.
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0.05, n = 8). Again, as with
spontaneous waves, exposure to 5 mM caffeine in the presence of
8-amino-cADPR produced an [Ca2+]i transient
with an amplitude not significantly different from the response to
electrical stimulation (84 ± 11%) prior to 8-amino-cADPR exposure.
Effect of ryanodine.
In quiescent myocytes (not paced or displaying spontaneous
[Ca2+]i waves) preexposed to 10 µM
ryanodine, the efficacy of RyR channel blockade was verified by lack of
an [Ca2+]i response to 5 mM caffeine. Under
these conditions, injection with 100 nM, 300 nM, or 1 µM cADPR did
not produce any elevation in [Ca2+]i.
However, injection of 3 µM cADPR produced a small
[Ca2+]i response (130 ± 56 nM
amplitude; Fig. 5A;
n = 6).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The present study demonstrates that cADPR induces concentration-dependent [Ca2+]i responses in rodent cardiac muscle. A considerable portion of the [Ca2+]i response to cADPR involves SR Ca2+ release through RyR channels; however, there appears to be a significant component of the response to cADPR that is not inhibited by high concentrations of ryanodine and is insensitive to caffeine. Furthermore, enhancement of the amplitude of the [Ca2+]i response to electrical stimulation, as well as frequency of spontaneous [Ca2+]i waves, suggests that cADPR potentiates the sensitivity of Ca2+-induced Ca2+ release.
Although the enzymes required for cADPR synthesis and degradation have been identified in cardiac muscle (13, 19) and endogenous levels have been estimated to be in the submicromolar range (21), the role of cADPR in cardiac muscle remains controversial. Several other studies have demonstrated specific cADPR-induced Ca2+ release from microsomes of the canine heart (8, 12), and the present study is consistent with these previous results. However, in contrast to the present and the previously mentioned studies, Guo et al. (4) found that flash photolysis of caged cADPR does not induce SR Ca2+ release in intact rat cardiac myocytes (4). On the other hand, Cui et al. (1) recently demonstrated that photoreleased cADPR potentiates whole cell [Ca2+]i transients as well as spontaneous Ca2+ sparks in both guinea pig and rat ventricular myocytes. The reasons for the discrepancies between these studies are unclear, but may be related to the relative efficacy of flash photolysis systems and differences in photoreleased vs. directly injected active cADPR.
Tissue differences in response to cADPR. In contrast to nonmuscle tissue such as sea urchin eggs, where a few nanomolars of cADPR are sufficient to elicit a robust [Ca2+]i response (9), relatively high cADPR concentrations were required in cardiac myocytes. However, it must be noted that previous studies in intact rabbit skeletal muscle (14), isolated canine cardiac SR vesicles (8), and guinea pig cardiac myocytes (1, 17) have also reported the use of micromolar, and sometimes millimolar, cADPR concentrations to elicit [Ca2+]i responses. The reasons for the vastly different cADPR concentrations required in different cell types are not clear. Furthermore, studies using photolysis of caged cADPR have not been consistent in reporting the actual extent of uncaging, and thus the actual cADPR concentration is not known.
When comparing across studies in cardiac muscle alone, a potential problem with interpreting results from microsomes is that any cytosolic, nonmembrane bound components of the cADPR pathway are lost. Furthermore, in canine cardiac microsomal preparations, micromolar (10-100 µM) concentrations of cADPR are required to induce Ca2+ release comparable to that elicited in the present study using nanomolar concentrations, again suggesting a loss in sensitivity during tissue processing. There is considerable evidence from other tissues for high-affinity cADPR binding sites in the SR membrane (3, 7, 9), which most likely mediate cADPR effects on [Ca2+]i. The present study did not directly examine whether cADPR binding sites also exist in rat cardiac muscle. However, their existence is strongly indicated by the concentration-dependent [Ca2+]i response to cADPR and the potent inhibition of the [Ca2+]i response by 8-amino-cADPR, a selective cADPR receptor antagonist. These results with 8-amino-cADPR are also consistent with previous studies in guinea pig cardiac myocytes (17, 18). It is possible that different cADPR receptor subtypes exist in different cell types and across species (akin to RyR channels), which vary in their binding affinity for cADPR, and may underlie the differences in sensitivity to cADPR. However, this issue remains to be examined. Another potential issue that has not been examined is the role of [Ca2+]i itself in the response to cADPR, which may underlie the discrepant results from various studies. For example, in longitudinal smooth muscle from rabbit intestine, Kuemmerle and Makhlouf (7) demonstrated that the cADPR-mediated Ca2+ release exhibits a "bell-shaped" dependence on [Ca2+]i, with a maximum activation at ~500 nM. The Ca2+ dependence of cADPR in cardiac muscle remains to be determined, although it is possible that maximum cADPR binding in this tissue also occurs at [Ca2+]i concentrations similar to those in smooth muscle. If so, this may explain, at least in part, the requirement for higher cADPR concentrations to elicit [Ca2+]i responses in cardiac muscle, most likely due to an apparently low affinity of cADPR binding at a resting Ca2+ concentration of ~100 nM. It is not clear whether this potential mechanism played a role in the results of previous studies, since basal [Ca2+]i levels were not reported. cADPR-mediated SR Ca2+ release is also highly sensitive to calmodulin, at least as demonstrated in sea urchin eggs (11). It is unknown whether calmodulin is required for cADPR-induced Ca2+ release in cardiac muscle. This issue will be examined in future studies using calmodulin and calmodulin kinase antagonists. As mentioned previously, the presence of cADPR synthesis and breakdown enzymes have been demonstrated in cardiac muscle. However, the relative activities of the ADP ribosyl cyclase and cADPR hydrolase have not been determined in cardiac muscle, and accordingly, the extent and rate of cADPR synthesis and hydrolysis may vary across cell types. Accordingly, higher concentrations of exogenous cADPR may be required to achieve a given concentration at the level of the cADPR binding site.Mechanisms of cADPR-induced SR Ca2+ release. Previous studies in different tissues have suggested that cADPR mediates Ca2+ release through RyR channels (3, 6, 9, 16, 20, 22). Indeed, a common target for both caffeine (or ryanodine) and cADPR has been demonstrated in sea urchin eggs (3, 9) and, recently, in porcine airway smooth muscle (16). However, unlike the direct effects of ryanodine, cADPR clearly influences RyR function indirectly, as demonstrated by the fact that even when the cADPR binding site is blocked by 8-amino-cADPR, the [Ca2+]i response to caffeine is unaffected. The indirect effects of cADPR on RyR channels most likely require intermediate proteins such as calmodulin, as demonstrated in other tissues.
The modulation of frequency of [Ca2+]i waves by cADPR and the abolition of waves by 8-amino-cADPR are both consistent with a recent report by Rakovic et al. (17) in the guinea pig ventricle, where they demonstrated that exogenous cADPR triggered spontaneous contractile activity, whereas 8-amino-cADPR suppressed not only the spontaneous waves, but also spontaneous action potentials, after-depolarizations, and transient inward currents. Since spontaneous Ca2+ waves are thought to arise from cyclical Ca2+-induced Ca2+ release from the SR, modulation of frequency suggests enhanced sensitivity of this mechanism in the presence of cADPR. In this regard, the increased amplitude of the [Ca2+]i response to electrical stimulation is also significant, where the amplitude reflects a summation of Ca2+ influx and Ca2+-induced Ca2+ release. A specific effect of cADPR on the SR component of this [Ca2+]i response is suggested by the fact that 8-amino-cADPR blunts the [Ca2+]i response to electrical stimulation, but a small component of the response persists, most likely reflecting Ca2+ influx. Although the results of the present study demonstrate an effect of cADPR on RyR channels, they also show that the [Ca2+]i response of rat cardiac myocytes to cADPR is not entirely through caffeine-sensitive RyR channels. For example, depletion of caffeine-sensitive SR Ca2+ stores does not completely abolish the cADPR-induced [Ca2+]i response, and 8-amino-cADPR does not completely abolish the [Ca2+]i response to caffeine. Interestingly, this is not the first demonstration of a cADPR-sensitive, but caffeine-insensitive, SR Ca2+ pool. Studies in rabbit skeletal muscle (14) and canine cardiac SR vesicles (8) have also demonstrated that specific blockers of RyR channels do not abolish cADPR-induced Ca2+ release. In the study on canine cardiac microsomes, Lahouratate et al. (8) proposed a model based on their data that cADPR-mediated SR Ca2+ release in cardiac tissue does not involve either RyR channels or caffeine-sensitive Ca2+ stores but that separate cADPR-sensitive channels and caffeine-insensitive Ca2+ stores exist. Interestingly, in a previous study in porcine coronary artery smooth muscle (6), we also demonstrated that cADPR induces SR Ca2+ release even when RyR channels were blocked by ryanodine. Furthermore, in coronary artery smooth muscle cells, depletion of caffeine-sensitive SR Ca2+ stores did not inhibit the [Ca2+]i response to cADPR. These results contrast with studies in porcine tracheal smooth muscle, where all of the cADPR effects appear to occur via RyR channels (16). Accordingly, it is possible that the relative roles of caffeine-sensitive and -insensitive SR Ca2+ pools differ between tissues and may underlie some of the discrepant findings in different studies. Whether there is any overlap between the caffeine-sensitive and -insensitive Ca2+ pools, or an interactive mechanism, remains to be determined. Furthermore, it is possible that all of the effects of cADPR are not at the SR alone and that additional effects on other Ca2+ homeostasis mechanisms underlie the ryanodine/caffeine-insensitive component of the [Ca2+]i response to cADPR. For example, in neuronal cell lines, Hashii et al. (5), demonstrated that cADPR enhances Ca2+ influx through voltage-gated channels. Whether such mechanisms play a role in cardiac myocytes remains to be determined.Physiological significance of cADPR in cardiac muscle. There is currently sparse information on the physiological role of cADPR in excitation-contraction coupling, partly due to the conflicting results on whether cADPR even induces an [Ca2+]i response in cardiac myocytes [e.g., Guo et al. (4) vs. Rakovic et al. (18) or Cui et al. (1)]. It has been proposed that cADPR concentrations are already sufficiently high to facilitate SR Ca2+ release in the heart, and therefore exogenous application of cADPR does not produce any additional release. However, the submicromolar concentrations of endogenous cADPR concentration in the rat heart (21) and the additional [Ca2+]i responses to exogenous cADPR argue against a saturation of cADPR effects under basal conditions. Furthermore, it is possible that with electrical stimulation, cADPR levels are increased and/or the sensitivity to cADPR-induced SR Ca2+ release is increased due to the elevation in [Ca2+]i produced by the stimulation. This may partially underlie the increase in the amplitude of the [Ca2+]i response to electrical stimulation upon exogenous cADPR administration. Facilitation of Ca2+-induced Ca2+ release from the SR has also been suggested by a recent study demonstrating modulation of Ca2+ sparks in ventricular myocytes (1). Furthermore, if cADPR induces Ca2+ release through both caffeine-sensitive and -insensitive stores, then it is possible the elevation in [Ca2+]i during electrical stimulation facilitates both Ca2+-induced Ca2+ release (via RyR channels) as well as release through the cADPR-sensitive channels.
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ACKNOWLEDGEMENTS |
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The research was supported by National Institutes of Health Grants GM-57816 (to Y. S. Prakash), HL-57498 (to M. S. Kannan), GM-56686 (to G. C. Sieck), and DA-11806 (T. F. Walseth) and by the Mayo Foundation.
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FOOTNOTES |
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Address for reprint requests and other correspondence: Y. S. Prakash, Anesthesia Research, 4-184 W. Joseph SMH, Mayo Clinic, Rochester, MN 55905 (E-mail: prakash.ys{at}mayo.edu).
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.
Received 3 January 2000; accepted in final form 27 April 2000.
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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