Departments of Anesthesiology and of Physiology and Biophysics, Mayo Foundation, Rochester 55905; and Departments of Veterinary PathoBiology, Pediatrics, and Pharmacology, University of Minnesota, St. Paul, Minnesota 55108
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ABSTRACT |
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The purpose of
the present study was to determine whether cyclic ADP-ribose (cADPR)
acts as a second messenger for
Ca2+ release through ryanodine
receptor (RyR) channels in tracheal smooth muscle (TSM). Freshly
dissociated porcine TSM cells were permeabilized with -escin, and
real-time confocal microscopy was used to examine changes in
intracellular Ca2+ concentration
([Ca2+]i).
cADPR (10 nM-10 µM) induced a dose-dependent increase in [Ca2+]i,
which was blocked by the cADPR receptor antagonist 8-amino-cADPR (20 µM) and by the RyR blockers ruthenium red (10 µM) and ryanodine (10 µM), but not by the inositol 1,4,5-trisphosphate receptor blocker
heparin (0.5 mg/ml). During steady-state
[Ca2+]i
oscillations induced by acetylcholine (ACh), addition of 100 nM and 1 µM cADPR increased oscillation frequency and decreased peak-to-trough
amplitude. ACh-induced
[Ca2+]i
oscillations were blocked by 8-amino-cADPR; however, 8-amino-cADPR did
not block the
[Ca2+]i
response to a subsequent exposure to caffeine. These results indicate
that cADPR acts as a second messenger for
Ca2+ release through RyR channels
in TSM cells and may be necessary for initiating ACh-induced
[Ca2+]i
oscillations.
ryanodine receptor; second messenger; confocal microscopy; sarcoplasmic reticulum; -escin; intracellular calcium concentration
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INTRODUCTION |
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SEVERAL STUDIES in a variety of tissues have shown that
cyclic ADP-ribose (cADPR), a metabolite of -NAD, can induce
sarcoplasmic reticulum (SR) Ca2+
release through ryanodine receptor (RyR) channels. However, cADPR does
not appear to directly activate RyR channels. Instead, the effect of
cADPR on Ca2+ release is
apparently mediated by high-affinity cADPR binding sites in the SR
membrane. Accordingly, it has been demonstrated that SR
Ca2+ release is inhibited by
8-amino-cADPR, a selective cADPR receptor antagonist. The concentration
dependence of the Ca2+ response to
cADPR appears to vary across tissues. For example, in sea urchin eggs,
where the Ca2+ response to cADPR
has been best characterized, the
Ca2+ response is saturated at
nanomolar concentrations. In contrast, in skeletal and cardiac muscles,
micromolar concentrations of cADPR are required to elicit maximal
Ca2+ responses.
The effect of cADPR on SR Ca2+ release in smooth muscle cells has been recently studied. In SR vesicles from intestinal smooth muscle, Kuemmerle and Makhlouf (9) demonstrated that cADPR induces Ca2+ release. Kuemmerle and Makhlouf also demonstrated the existence of such high-affinity cADPR binding sites in intestinal smooth muscle. In permeabilized coronary artery smooth muscle cells, we demonstrated that cADPR induces SR Ca2+ release even in the presence of heparin. However, in coronary artery smooth muscle, ryanodine blockade of RyR channels did not completely inhibit cADPR-induced Ca2+ release. Furthermore, depletion of the caffeine-sensitive SR Ca2+ stores did not prevent the Ca2+ response to cADPR. Thus we concluded that cADPR-induced Ca2+ release in coronary artery smooth muscle is not mediated solely by RyR channels.
Recently, we and others have shown that activation of muscarinic receptors in porcine tracheal smooth muscle (TSM) cells by acetylcholine (ACh) results in oscillations in intracellular Ca2+ concentration ([Ca2+]i). These ACh-induced [Ca2+]i oscillations in TSM cells persist even when SR Ca2+ release through inositol 1,4,5-trisphosphate (IP3) receptors is inhibited by heparin. Furthermore, ACh-induced [Ca2+]i oscillations in TSM cells are inhibited by ruthenium red, which blocks RyR channels. Therefore, we concluded that ACh-induced [Ca2+]i oscillations in TSM cells arise from repetitive release of SR Ca2+ through RyR channels. However, the second messenger involved in triggering Ca2+ release through RyR channels in TSM cells remains to be determined.
The purpose of the present study was to examine whether cADPR induces SR Ca2+ release in porcine TSM cells. The role of RyR channels in the [Ca2+]i response to cADPR was investigated. Furthermore, the modulation of ACh-induced [Ca2+]i oscillations in TSM cells by cADPR was assessed.
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METHODS |
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Cell preparation. Porcine tracheas were obtained from a local abattoir. Single TSM cells were isolated using techniques described previously. Briefly, the tissue was minced in Hanks' balanced salt solution (HBSS) containing 10 mM glucose and 10 mM HEPES (pH 7.4). The tissue was then incubated first in 20 U/ml papain and 2,000 U/ml DNase and subsequently in 1 mg/ml type IV collagenase (Worthington Biochemical, Freehold, NJ). TSM cells were released by trituration, centrifuged, and suspended in minimum essential medium containing 10% FCS.
Confocal [Ca2+]i imaging. Dissociated TSM cells were plated on glass coverslips coated with rat tail collagen and incubated for 1-2 h at 37°C in 5% CO2. The cells were used for experiments at 2-16 h after plating. Exclusion of trypan blue was used to determine cell viability (>90%). Some cell samples were reacted with anti-smooth muscle myosin antibody (Sigma Chemical, St. Louis, MO) to determine the relative proportions of myocytes and fibroblasts (~50:1 ratio).
Coverslips with attached TSM cells were incubated in 5 µM 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 HBSS at 2-3 ml/min at room temperature. Detailed techniques for real-time confocal imaging of [Ca2+]i in TSM cells have been recently described. Briefly, 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. Although the confocal system was capable of acquiring images at 480 frames/s, in previous studies we determined that a rate of 30 frames/s was sufficient to determine the dynamic [Ca2+]i response of TSM cells without frequency aliasing (the appearance of higher-frequency signals being of lower frequency because of inadequate data sampling). An Olympus ×40, 1.3 numerical aperture, 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 of 5 × 5 pixels (1.5 µm2), [Ca2+]i measurements were obtained from volumes of 1.5 µm3. On the basis of previous calibrations of [Ca2+]i in TSM cells, 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 regions of interest ranged from 25 to 255 gray levels. In intact TSM cells the gray level data were converted to nanomolar Ca2+ on the basis of a previously described calibration procedure. However, in-Escin-permeabilized cell preparation.
In previous studies on intact and
-escin-permeabilized TSM cells, we
determined that the EC50 for the
[Ca2+]i
response to ACh was ~1 µM. Therefore, a fixed concentration of 1 µM ACh was used in the present study. Intact TSM cells were first
exposed to 1 µM ACh, and the initiation of
[Ca2+]i
oscillations was verified. The same cells were then washed in HBSS for
15 min and permeabilized by exposure to 25 µM
-escin (Sigma
Chemical) in a pCa 9.0 solution for ~1 min. Adequate cell permeabilization was confirmed by a
[Ca2+]i
response to IP3, which is excluded
in intact cells. After permeabilization the cells were washed with pCa
9.0 solution for 2 min. The SR was then loaded by incubating the cells
for 10-15 min in pCa 7.0 solution.
[Ca2+]i
response to cADPR.
In initial studies on 10 -escin-permeabilized TSM cells we found
that the
[Ca2+]i
response to 1 µM cADPR was not reproducible but displayed substantial decrement with repeated exposures. Therefore, it was not possible to
analyze the concentration dependence of the
[Ca2+]i
response to cADPR within a single cell. Instead, cells were exposed to
one of four concentrations of cADPR (10 nM, 100 nM, 1 µM, or 10 µM), and the mean
[Ca2+]i
response for each cADPR concentration was determined.
Effects of RyR channel blockade on
[Ca2+]i
response to cADPR.
-Escin-permeabilized cells were preexposed to 10 µM ruthenium red
to inhibit RyR channels. The cells were then exposed to cADPR. In a
second set of experiments, permeabilized TSM cells were preexposed to
10 µM ryanodine to block RyR channels, and the cells were
subsequently exposed to 1 µM cADPR. In both cases the efficacy of
channel blockade was confirmed by exposing the same cells to 5 mM
caffeine. In a third set of experiments, permeabilized TSM cells were
preexposed to 5 mM caffeine to deplete caffeine-sensitive SR stores.
The cells were then exposed to 1 µM cADPR.
Effects of IP3 receptor channel blockade
on
[Ca2+]i
response to cADPR.
The
[Ca2+]i
response to 1 µM IP3 was
evaluated in one set of -escin-permeabilized TSM cells. A second set
of permeabilized cells was preexposed for 15 min to 0.5 mg/ml heparin
to block IP3 receptor channels.
The cells were then exposed to 1 µM
IP3 to verify efficacy of heparin
in blocking IP3 receptor channels. The cells were finally exposed to 1 or 10 µM cADPR.
Effects of cADPR receptor antagonist on
[Ca2+]i
response to cADPR.
-Escin-permeabilized TSM cells were preexposed for 15 min to 20 µM
8-amino-cADPR, a selective antagonist of the cADPR receptor. The
[Ca2+]i
response to cADPR was then evaluated. In the continued presence of
cADPR and 8-amino-cADPR, the cells were finally exposed to 5 mM
caffeine. In a second set of experiments,
-escin-permeabilized TSM
cells were preexposed to 8-amino-cADPR and 10 µM ruthenium red or 10 µM ryanodine to block RyR channels. The cells were exposed to cADPR
and finally to caffeine.
Effect of cADPR on ACh-induced
[Ca2+]i
oscillations.
In intact TSM cells,
[Ca2+]i
oscillations were induced by exposure to 1 µM ACh. As previously
described, these ACh-induced
[Ca2+]i
oscillations displayed an initial dynamic phase characterized by faster
oscillation frequency and lower peak-to-trough amplitude because of an
elevation of basal
[Ca2+]i.
After ~90 s the ACh-induced
[Ca2+]i
oscillations reached a steady-state phase characterized by lower
relatively constant oscillation frequency and higher peak-to-trough amplitude. The TSM cells were then permeabilized by exposure to -escin, and
[Ca2+]i
oscillations were induced by exposure to 1 µM ACh and 10 µM GTP.
After ~90 s the cells were exposed to different concentrations of
cADPR in the continued presence of ACh and GTP.
Statistical analysis. [Ca2+]i responses were evaluated for a total of 216 TSM cells. The specific number of cells analyzed for each protocol is provided in RESULTS. Data were compared using Student's t-tests. Statistical significance was tested at a 0.05 level.
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RESULTS |
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[Ca2+]i
response to cADPR.
In -escin-permeabilized TSM cells, exposure to cADPR induced a
[Ca2+]i
response that was concentration dependent (Figs.
1 and
2). Exposure to 10 nM
(n = 10) and 100 nM
(n = 10) cADPR did not induce any
appreciable change in
[Ca2+]i
(4 ± 1% and 6 ± 1% increase, respectively). However, exposure to 1 µM (n = 10) and 10 µM
(n = 10) cADPR induced a robust
transient [Ca2+]i
response (245 ± 24% and 419 ± 31% increase, respectively).
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Effects of RyR channel blockade on
[Ca2+]i
response to cADPR.
The
[Ca2+]i
response of -escin-permeabilized TSM cells to cADPR was abolished by
blocking RyR channels. For example, preexposing permeabilized TSM cells
(n = 8) to 10 µM ruthenium red
abolished the
[Ca2+]i
response to 1 µM cADPR (Fig.
3A).
Similarly, preexposing permeabilized TSM cells
(n = 8) to 10 µM ryanodine abolished
the
[Ca2+]i
response to 1 µM cADPR (Fig. 3B). In both cases, the efficacy of RyR channel blockade was confirmed by the lack of a
[Ca2+]i
response to 5 mM caffeine (Fig. 3, A
and B).
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Effects of IP3 receptor channel blockade
on
[Ca2+]i
response to cADPR.
In -escin-permeabilized TSM cells
(n = 8), exposure to 1 µM
IP3 induced a prolonged
[Ca2+]i
response (Fig.
4A).
Preexposing permeabilized TSM cells to 0.5 mg/ml heparin completely
inhibited the
[Ca2+]i
response to 1 µM IP3 (Fig.
4B) but had no effect on the
[Ca2+]i
response to 1 µM cADPR (n = 10; Fig.
4C) and 10 µM cADPR
(n = 10; Fig.
4D).
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Effects of cADPR receptor antagonist on
[Ca2+]i
response to cADPR.
The
[Ca2+]i
response of -escin-permeabilized TSM cells to cADPR was abolished by
blocking cADPR binding sites with 20 µM 8-amino-cADPR (n = 22; Fig.
5A).
However, 8-amino-cADPR did not inhibit the [Ca2+]i
response to a subsequent exposure to 5 mM caffeine (Fig.
5A). On the other hand, in the
presence of 20 µM 8-amino-cADPR, the [Ca2+]i
response of permeabilized TSM cells to 5 mM caffeine was abolished by
10 µM ruthenium red (n = 10; Fig.
5B) or 10 µM ryanodine
(n = 10; Fig.
5C).
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Effect of cADPR on ACh-induced
[Ca2+]i
oscillations.
After -escin permeabilization and SR reloading with pCa 7.0 solution, exposure to 1 µM ACh and 10 µM GTP induced propagating [Ca2+]i
oscillations that were qualitatively similar to the steady-state oscillations observed in intact cells before permeabilization (n = 74). At the steady-state level
the amplitude of ACh-induced [Ca2+]i
oscillations in intact cells was between 100 and 700 nM (463 ± 11 nM). Assessment of nanomolar Ca2+
levels in
-escin-permeabilized TSM cells was not possible because of
uncontrolled leakage of fluo 3; however, substantial
[Ca2+]i
oscillations above baseline could be readily observed. The steady-state
frequency of the ACh-induced
[Ca2+]i
oscillations in intact and permeabilized cells was 10-25
min
1 (19 ± 2 min
1).
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DISCUSSION |
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The present study demonstrates that cADPR induces SR Ca2+ release through RyR channels in porcine TSM cells. In previous studies, ACh-induced [Ca2+]i oscillations have been shown to occur through repetitive SR Ca2+ release through RyR channels. The present study suggests that the RyR channel is the mechanistic link between cADPR- and ACh-induced [Ca2+]i oscillations in porcine TSM cells.
In the present study, SR Ca2+
release under Ca2+-clamped
conditions was examined using -escin-permeabilized TSM cells. This
procedure has been previously used in intact smooth muscle strips and
single smooth muscle cells to facilitate intracellular access to
relatively high-molecular-weight substances, such as heparin, and to
investigate receptor-signal transduction pathways. In the present study
the integrity of the receptor-signal transduction pathways in
-escin-permeabilized TSM cells and the extent of permeabilization
were confirmed by the
[Ca2+]i
response to IP3, which is excluded
by intact cells.
There is considerable evidence from non-smooth muscle tissue for high-affinity cADPR binding sites in the SR membrane. Recently, Kuemmerle and Makhlouf (9) also demonstrated the existence of such high-affinity cADPR binding sites in intestinal smooth muscle. The present study did not directly examine whether cADPR binding sites also exist in porcine TSM cells. However, their existence is suggested by the concentration-dependent [Ca2+]i response to cADPR and the inhibition of the [Ca2+]i response by 8-amino-cADPR, a selective cADPR receptor antagonist.
In contrast to nonmuscle tissue such as sea urchin eggs, a relatively
high concentration (micromolar) of cADPR was required to elicit
[Ca2+]i
responses in -escin-permeabilized TSM cells. However, it must be
noted that previous studies in intact skeletal muscle and isolated cardiac SR vesicles have also reported the use of micromolar cADPR concentrations to elicit
[Ca2+]i
responses. The reasons for the vastly different cADPR concentrations required in different cell types are not clear. It is possible that
different cADPR receptor subtypes exist in different cell types (akin
to RyR channels) that vary in their binding affinity for cADPR. There
is no information to support the presence of different cADPR receptor
subtypes.
In several cell types it has been demonstrated that the [Ca2+]i response to cADPR depends on [Ca2+]i. For example, in intestinal smooth muscle, Kuemmerle and Makhlouf (9) also demonstrated that the cADPR-mediated Ca2+ release exhibits a "bell-shaped" dependence on [Ca2+]i, much like the IP3 receptor channel, with a maximum activation at ~500 nM. The Ca2+ dependence of cADPR in TSM remains to be determined. However, it is possible that maximum cADPR binding in TSM cells also occurs at [Ca2+]i similar to those in intestinal smooth muscle. If so, this may explain, at least in part, the requirement for higher cADPR concentrations to elicit [Ca2+]i responses in TSM cells because of an apparently low affinity of cADPR binding at 100 nM Ca2+ (pCa 7.0) in the present study.
In sea urchin eggs, calmodulin increases the sensitivity of cADPR-mediated SR Ca2+ release by several orders of magnitude. If calmodulin is required for cADPR-induced Ca2+ release in TSM cells, the process of permeabilization may have led to some loss of calmodulin from the cell, thus decreasing the sensitivity of the [Ca2+]i response to cADPR.
Another important factor that may have influenced the concentration dependence of the [Ca2+]i response to cADPR is the presence of cADPR hydrolase as well as hydrolytic activity associated with CD38. These hydrolytic mechanisms are apparently ubiquitous, but the extent and rate of cADPR 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.
Previous studies have suggested that cADPR mediates Ca2+ release through RyR channels. In agreement with these studies, the [Ca2+]i response of TSM cells to cADPR was blocked by ruthenium red and ryanodine, but not by heparin. Furthermore, depletion of caffeine-sensitive SR Ca2+ stores abolished the cADPR-induced [Ca2+]i response in TSM cells. However, it appears that RyR channel activation is not an exclusive mechanism underlying cADPR-induced Ca2+ release across cell types. For example, in a previous study in porcine coronary artery smooth muscle, we demonstrated that cADPR induced 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. Studies in skeletal muscle and canine cardiac SR vesicles have also demonstrated that specific blockers of RyR channels did not abolish cADPR-induced Ca2+ release. Lahouratate et al. (10) proposed that cADPR-mediated SR Ca2+ release in cardiac tissue does not involve RyR channels or caffeine-sensitive Ca2+ stores but that separate cADPR-sensitive channels and caffeine-insensitive Ca2+ stores exist. These discrepancies clearly indicate cell-specific differences in the mechanisms underlying cADPR-mediated [Ca2+]i regulation.
The results of the present study suggest that, in TSM cells, cADPR indirectly activates RyR channels. For example, in the presence of 8-amino-cADPR, caffeine still induced a [Ca2+]i response in TSM cells. This [Ca2+]i response to caffeine was blocked by ruthenium red and ryanodine. Although these results clearly suggest that cADPR indirectly activates RyR channels, it was not feasible to directly test this hypothesis with use of the current protocols. An alternate possibility is that cADPR directly activates RyR channels by binding to a site different from that of caffeine. However, previous reports in which photoaffinity labeling of cADPR receptors was used indicate cADPR binding sites that are distinct from the RyR channel itself. Furthermore, RyR channel activation by cADPR appears to require the involvement of other proteins, such as calmodulin. Lee and colleagues (12) suggested that cADPR receptors may be coupled to RyR in sea urchin eggs through an intermediate protein. It is unknown whether such intermediate proteins exist in TSM cells. Nonetheless, it appears likely that cADPR indirectly activates RyR channels in TSM cells, perhaps facilitating Ca2+-induced Ca2+ release through these channels.
In porcine TSM cells, ACh induces repetitive
[Ca2+]i
oscillations that arise from SR
Ca2+ release rather than
Ca2+ influx. In
-escin-permeabilized TSM cells, ACh also induced [Ca2+]i
oscillations that were qualitatively similar to the steady-state phase
of oscillations in intact TSM cells. In permeabilized TSM cells,
[Ca2+]i
oscillations were inhibited when RyR channels were blocked by ruthenium
red, but not by heparin. Therefore, we concluded that ACh-induced
[Ca2+]i
oscillations in porcine TSM cells represent repetitive SR
Ca2+ release through RyR channels.
The results of the present study extend these previous observations by
demonstrating that the cADPR receptor antagonist 8-amino-cADPR also
inhibits ACh-induced
[Ca2+]i
oscillations in TSM cells. These results suggest that cADPR may play an
important role in the initiation and maintenance of ACh-induced
[Ca2+]i
oscillations in TSM cells.
In a previous study we found that, although exposing
-escin-permeabilized TSM cells to heparin did not block ongoing
ACh-induced [Ca2+]i
oscillations, preexposure to heparin inhibited the initiation of
oscillations. On the basis of our previous results, we concluded that
there is a link between ACh-stimulated
Ca2+ release through
IP3 receptors and the initiation
of
[Ca2+]i
oscillations mediated through RyR channels. ACh-induced SR Ca2+ release through
IP3 receptor channels may elevate
basal
[Ca2+]i
levels, thereby facilitating cADPR-mediated RyR activation. In support
of this theory, it has been demonstrated that cADPR binding to its
receptor and RyR activation are
Ca2+ sensitive. In SR vesicles
derived from rabbit intestinal smooth muscle, it was shown that maximal
cADPR-induced Ca2+ release
occurred at a basal Ca2+
concentration of ~500 nM. Thus, at resting basal
[Ca2+]i
within TSM cells (~100 nM), cADPR receptor binding and RyR channel
activation are not maximally sensitized.
IP3-mediated SR
Ca2+ release would elevate the
local
[Ca2+]i
and thus sensitize cADPR receptor binding and RyR channel activation. The rapid rise time of the cADPR-induced
[Ca2+]i
response, as well as the ACh-induced
[Ca2+]i
oscillations, may reflect such a positive-feedback mechanism.
It is possible that ACh stimulation may regulate cADPR levels, akin to IP3 levels, and thus cADPR may act as a second messenger for RyR activation in TSM cells. Alternatively, it is possible that relatively high cADPR levels are present, even in the unstimulated cell, and that cADPR facilitates RyR channel activation once agonist stimulation elevates basal [Ca2+]i via other mechanisms, such as IP3-induced SR Ca2+ release and Ca2+ influx. To discern among these possibilities, the effect of agonist stimulation on cADPR levels needs to be explored in TSM cells.
In conclusion, the present study clearly demonstrated that cADPR induces SR Ca2+ release through RyR channels in porcine TSM cells via a receptor-mediated mechanism. During ACh-induced [Ca2+]i oscillations, cADPR may serve to facilitate RyR activation. The precise mechanisms by which cADPR interacts with RyR channels in TSM cells remain to be explored.
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ACKNOWLEDGEMENTS |
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The authors are grateful to Thomas Keller for technical assistance in cell preparation.
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FOOTNOTES |
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The research was supported by National Institutes of Health Grants HL-51736 and DA-08131, the Mayo Foundation, and the University of Minnesota Graduate School. Y. S. Prakash is supported by a fellowship from Abbott Laboratories.
Address for reprint requests: G. C. Sieck, Anesthesia Research SMH, Mayo Clinic, Rochester, MN 55905.
Received 17 March 1997; accepted in final form 20 February 1998.
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