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1 Department of Physiology, Nagoya City University Medical School, Nagoya 467-8601; and 2 Department of Pharmacology, Juntendo University School of Medicine, Tokyo 113-8421, Japan
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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The type 1 ryanodine
receptor (RyR1) from rabbit skeletal muscle displayed two distinct
degrees of response to cytoplasmic Ca2+ [high- and
low-open probability (Po) channels]. Here, we
examined the effects of adenine nucleotides and caffeine on these
channels and their modulations by sulfhydryl reagents.
High-Po channels showed biphasic
Ca2+ dependence and were activated by adenine nucleotides
and caffeine. Unexpectedly, low-Po channels did
not respond to either modulator. The addition of a reducing reagent,
dithiothreitol, to the cis side converted the
high-Po channel to a state similar to that of
the low-Po channel. Treatment with
p-chloromercuriphenylsulfonic acid (pCMPS) transformed
low-Po channels to a
high-Po channel-like state with stimulation by
,
-methylene-ATP and caffeine. In experiments under redox control
using glutathione buffers, shift of the cis potential toward
the oxidative state activated the low-Po
channel, similar to that of the high-Po or the
pCMPS-treated channel, whereas reductive changes inactivated the
high-Po channel. Changes in trans
redox potential, in contrast, did not affect channel activity of
either channel. In all experiments, channels with higher
Po were stimulated to a great extent by
modulators, but ones with lower Po were
unresponsive. These results suggest that redox states of critical
sulfhydryls located on the cytoplasmic side of the RyR1 may alter both
gating properties of the channel and responsiveness to channel modulators.
calcium-induced calcium release; adenine nucleotide; caffeine; sulfhydryl reagents; redox potential
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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RELEASE OF CA2+ FROM intracellular Ca2+ stores plays a crucial role in regulation of intracellular Ca2+, which serves as a second messenger for many intracellular signaling processes. The ryanodine receptor (RyR) is one of the Ca2+ release channels located on the endoplasmic or sarcoplasmic (SR) reticulum (11, 26, 36). Three isoforms of RyRs (RyR1-3) have been identified in mammalian tissues (26, 36). All of the RyRs demonstrate Ca2+-induced Ca2+ release (CICR) activity, which is modulated by many endogenous and exogenous ligands (4, 14, 17, 20, 26, 27, 33, 38, 41). The RyR channel is activated by Ca2+ in micromolar amounts and by adenine nucleotides and caffeine but is inhibited by Ca2+ in the millimolar order and by Mg2+.
A number of studies have demonstrated that oxidation,
S-nitrosylation, or alkylation of the critical sulfhydryls
in RyR molecules activates Ca2+ release channel activity,
whereas their reduction inhibits it (1, 3, 8-10, 12, 17, 24,
25, 31, 35, 36, 40). Heavy metals such as Hg2+ and
Ag+ have also been reported to activate RyR probably by
directly interacting with sulfhydryls, although there is a difference
in the chemical reaction between heavy metal binding and oxidation or
alkylation of sulfhydryls (2, 31). It has been proposed that the RyR molecule is a redox sensor with a well-defined redox potential (10, 39). In skeletal muscles, the RyR1 channel possesses heterogeneous populations differing in response to cis Ca2+ concentrations, when incorporated into lipid
bilayers (5, 18, 21). Channels termed
"high-Po" show biphasic Ca2+
dependence with relatively high open probability
(Po), and channels termed
"low-Po" display much lower activity, even
at an optimal Ca2+ concentrations, although
Ca2+ is also required for its activation. We have recently
reported that high-Po channels were inhibited by
a sulfhydryl-reducing agent, dithiothreitol (DTT), whereas
low-Po channels were activated by a
sulfhydryl-modifying reagent, p-chloromercuriphenylsulfonic acid (pCMPS; see Ref. 21). The stimulatory effect of pCMPS
was reversed by subsequent addition of DTT. In addition to channel gating, several effects of redox modification on the RyR channels have
been reported (7, 18). Marengo et al. (18)
demonstrated that the redox state of the channel molecule is a decisive
factor in determining the Ca2+ dependence. Donoso et al.
(7) recently reported that oxidation of RyR1 released the
inhibitory effect of Mg2+, resulting in activation of CICR.
These findings indicate that the redox state of the sulfhydryl residues
in RyR1 molecules may have an important impact on the modulation of
channel activity. However, it remains to be elucidated whether redox
states alter the stimulatory effects of CICR modulators, such as
adenine nucleotides and caffeine. Glutathione (GSH) and glutathione
disulfide (GSSG) constitute the major redox buffer system of many
cells, including skeletal muscle (32). The intracellular
redox potential in resting skeletal muscle fibers is maintained in a
highly reduced state of 
220 to 230 mV (13), although
the intraluminal side of the SR has been reported to be in an oxidized
state (approximately 180 mV; see Ref. 10). Intracellular
ATP content and GSH concentration ([GSH])-to-GSSG concentration
([GSSG]) ratio are known to be altered depending on exercise strength
(16, 19, 32). Therefore, it is of interest to study
whether redox states of the RyR molecule affect responses to CICR
modulators such as adenine nucleotides and caffeine, as well as
Ca2+.
In the present study, we examined the effects of redox reagents on RyR1 channel activity and its modulations by adenine nucleotide and caffeine, using a lipid bilayer technique. Attention was also directed to the effect of cis and/or trans redox potentials on the RyR1 channel behavior and its modulation by channel modulators by using a [GSH]/[GSSG] redox buffer. Our present results suggest that the cytoplasmic redox potential primarily determines RyR1 channel activity and its responsiveness to channel modulators.
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MATERIALS AND METHODS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Isolation of SR vesicles and purification of RyR1.
Heavy SR vesicles were prepared from rabbit back skeletal muscle in the
presence of a cocktail of protease inhibitors (in µg/ml: 2 aprotinin,
2 leupeptin, 1 antipain, 2 pepstatin A, and 2 chymostatin), as shown
elsewhere (23). RyR1 was purified using sucrose gradients
and Mono-Q anion exchange column chromatography (22).
Purified RyR 1 was free from FK506 binding protein (FKBP12) but
retained the ability to bind FKBP12 (21). The
preparations were quickly frozen in liquid N2 and stored at
80°C until use.
Planar lipid bilayer experiments.
Single-channel recordings were carried out by incorporating purified
RyR1 channels into planar lipid bilayers, as reported previously
(21, 24, 25). Lipid bilayers consisting of a mixture of
L-
-phosphatidylethanolamine,
L--phosphatidyl-L-serine, and
L--phosphatidylcholine (5:3:2 wt/wt/wt) in n-decane (40 mg/ml) were formed across a hole of ~250 µm in diameter in a
polystyrene partition separating cis and trans
chambers. The cis (1 ml)/trans (1.5 ml)
solutions consisted of 500/50 mM KCl, 20 mM HEPES/Tris (pH 7.4), and
0.1 mM CaCl2. Channel proteins were added to the cis
chamber. After confirming channel incorporation by the occurrence of flickering currents, further incorporation of channels was prevented
by adding an aliquot of 3 M KCl (pH was adjusted to 7.4 by 20 mM
HEPES/Tris) to the trans compartment. Recording of channel
currents was carried out in a symmetrical solution containing 500 mM
KCl, 20 mM HEPES/Tris (pH 7.4), and various concentrations of
Ca2+. The trans side was held at ground
potential, and the cis side was clamped at 40 mV using
1.5% agar bridges in 3 M KCl and Ag-AgCl electrodes. The cytoplasmic
surface of the RyR faced the cis side, as determined by
application of ATP or EGTA (24, 25). Channel activity
ascribed to RyR was confirmed by the responses to ryanodine and
ruthenium red at the end of every experiment. Experiments under redox
control of the cis and/or trans compartments were performed using a [GSH]/[GSSG] buffer solution. Redox potential in
the solution was calculated from the Nernst equation (13) by using the standard redox potential (= 0.24 V). Redox potentials were generated by the following different ratios of [GSH]/[GSSG] (mM/mM): 2:0.469 for 180 mV, 2:0.0196 for 220 mV, and 2:0.0082 for
231 mV. When redox potentials were changed consecutively, shift of
the redox potential from 220 mM to 231 mV was made by addition of
1.096 mM GSH and then to 180 mV by further addition of 1.103 mM GSSG.
Experiments were carried out at room temperature (18-22°C).
Chemicals.
Caffeine (500 mM; Sigma, St. Louis, MO), pCMPS (10 mM; Sigma), GSH (250 mM; Sigma), and GSSG (50 mM; Sigma) were prepared in ultrapure water
(Barnstead, Boston, MA) just before application. Stock solutions of ATP
(disodium salt, 100 mM; Sigma), ,-methylene-ATP (AMPPCP, disodium
salt, 100 mM; Sigma), and ruthenium red (1 mM; Sigma) were prepared in
water and stored at 20°C. Ryanodine (1 mM; Wako Pure Chemical,
Osaka, Japan) was dissolved in ethanol and stored at 20°C. Other
reagents were of analytical grade.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Low-Po and high-Po channels of RyR1.
When active RyR1 molecules, which showed a maximal binding of 1 mol
[3H]ryanodine/1 mol tetramer for
[3H]ryanodine binding, were incorporated into lipid
bilayers, the channels belonged to several distinct populations with
different Po at pCa 4. The results of 123 channels examined are summarized in Table
1. For easy analysis, we conveniently
classified channels into two groups. Channels with
Po 
0.05 at pCa 4.0 were referred to as
low-Po channels, and ones with
Po > 0.05 were referred to as
high-Po channels. The average
Po values for low-Po and
high-Po channels were 0.019 ± 0.005 (n = 78) and 0.263 ± 0.025 (n = 45), respectively. A clear Ca2+ dependence was not observed
in low-Po channels with
Po<0.01, because the number of open events was
below the analytical limit of our method. However, these channels also
exhibited null activity at Ca2+ concentrations <10 nM.
Low-Po channels with 0.01 < Po 0.05 showed the biphasic
Ca2+ dependence with a peak value around pCa 4.0 (Fig.
1A) and null activity at pCa
>8 (data not shown).
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O1 = 0.44 ms (80.2%
in relative area) and O2 = 2.27 ms (19.8%). The
low-Po channel after exposure to 50 µM pCMPS
displayed a new, third time constant of O3 = 7.81 ms (9.2%) in addition to two time constants of O1 = 0.34 ms (53.0%) and O2 = 1.73 ms (37.8%). The
closed time distribution was best fit by three exponentials with
similar values between channels. In addition to the occurrence of the
long open time constant, another characteristic was a significant
decrease in the relative area of O1 and an increase in
that of O2. Application of pCMPS to the
low-Po channel caused prolongation of the open
time, which may account for the increase in Po.
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Redox reagents and gating behavior of low- and high-Po
channels.
When applied to the cis compartment, 10 µM pCMPS slightly
activated the low-Po channel in the presence of
10 µM cis Ca2+ (Fig.
4A). An increase in pCMPS to
50 µM induced an ~20-fold increase in the Po
to 0.243. Results obtained using pCMPS over a range of 1-500 µM
are summarized in Fig. 4C. Two out of six channels examined
showed increased Po on exposure to pCMPS as low
as 10 µM, with an average of 0.027 ± 0.019 (n = 6). An increase in pCMPS to 25 µM significantly increased the
Po to 0.092 ± 0.030 (n = 4; P < 0.05), indicating that the threshold
concentration of pCMPS required for activation of the
low-Po channel is near 10 µM, although there
was a large channel-to-channel variation. Figure 4C shows
that the EC50 of pCMPS was ~26 µM. The
high-Po channel was also sensitive to pCMPS
(Po = 0.111 ± 0.075 in controls in
pCa 6, 0.132 ± 0.096 in 5 µM pCMPS, and 0.273 ± 0.106 in
50 µM, n = 5), suggesting that it was more sensitive
than the low-Po channel.
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Effects of adenine nucleotides and caffeine on low- and
high-Po channels with or without redox reagent treatment.
When added to the cis side of the
low-Po channel, AMPPCP, a nonhydrolyzable analog
of ATP, did not alter channel activity in 10 µM Ca2+
(Fig. 5A). In the presence of
3 mM AMPPCP, subsequent addition of 10 mM caffeine also failed to
activate this channel. In contrast, the high-Po
channel in pCa 6 (Po = 0.010) responded to
3 mM AMPPCP with an ~10-fold increase in Po
(Fig. 5B). Subsequent exposure to 10 mM caffeine further
increased the Po to 0.461, indicating a
potentiating action of adenine nucleotide and caffeine. In separate experiments, substituting 1 mM ATP for AMPPCP similarly stimulated high-Po channels (Po = 0.072 ± 0.020 at pCa 6 to 0.332 ± 0.045, n = 5) but had no effects on low
Po (Po = 0.007 ± 0.002 at pCa 5 to 0.007 ± 0.002, n = 3).
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Effects of redox potentials on low- and high-Po
channels and response to adenine nucleotide.
Until now, we have described the results of experiments where redox
reagents were added on the cis side alone. A recent study, however, indicated that the redox potential difference between cis and trans sides is critical for channel
activity. In that study (10), application of the reagents
to the cis side alone did not affect activity. Thus we
performed separate experiments under redox control using a
[GSH]/[GSSG] redox buffer (see MATERIALS AND METHODS).
The Po of low-Po channels
was markedly increased by defining cis redox potential at
180 mV (0.004 ± 0.003 in control to 0.079 ± 0.015, n = 3; Fig.
8A). Subsequent fixation of
the trans potential at 180 mV (a symmetrical
cis/trans potential of 180 mV), however, did not affect
channel activity (0.070 ± 0.002; Fig. 8A). The channel
activity was increased further to Po = 0.161 ± 0.061 (n = 3) on subsequent addition of
0.3 mM AMPPCP (Fig. 8A). In contrast, when trans
potential was set to 180 mV without defining cis
potential, the effect on Po was negligible (0.004 ± 0.003 before redox fixation to 0.015 ± 0.008, n = 7). Under this condition, Po
was increased by fixation of the cis potential at 180 mV
(0.069 ± 0.010, n = 3). Fixation of the cis potential at 220 mV instead of 180 mV did not affect the
channel activity, irrespective of the trans potential
(undefined or 180 mV; Po = 0.010 ± 0.006 to 0.013 ± 0.006, n = 4). These results strongly indicate that activation of low-Po
channels is primarily caused by the cis potential.
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180 mV (0.118 ± 0.045 in undefined control to 0.080 ± 0.045, n = 7; Fig. 8B). Subsequent reduction of the cis
potential to 220 mV had a minor effect on
Po (0.122 ± 0.051). Further reduction in
the cis potential to 231 mV drastically decreased the
Po (0.012 ± 0.007; Fig. 8B).
Under this condition, AMPPCP up to 3 mM failed to enhance
Po of the channel further (0.012 ± 0.007 at 0.3 mM AMPPCP and 0.016 ± 0.012 at 3 mM AMPPCP), as is true
with the low-Po channel and the DTT-treated
high-Po channel. These observations indicate
that the channel activity of the high-Po channel
also may be mainly determined by cis redox potential.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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The present study provides evidence that 1) transition between low-Po and high-Po states of skeletal muscle RyR1 channels is primarily regulated by the cytoplasmic redox potential alone, which may be caused by oxidation/reduction of critical sulfhydryls of the channel rather than by trans potential or transmembrane redox potential gradients, 2) pCMPS and DTT may act via these sulfhydryls on the cis side of the channel, and 3) a marked reduction in these sulfhydryls on the RyR molecule makes the channel unresponsive to CICR modulators such as adenine nucleotide and caffeine, whereas an oxidation leads to increased responsiveness to modulators.
When redox potentials were defined using a [GSH]/[GSSG] buffer, the
low-Po channel was markedly activated by setting
cis redox potential to 180 mV but was affected negligibly
at 220 mV (Fig. 8). High-Po channel activity
was not significantly altered at a cis redox potential of
220 mV but was inhibited markedly by the decrease from 220 to 231
mV. On the other hand, defining the trans redox potential to
180 mV under the control of cis redox potential failed to
affect low-Po or high-Po
channel activity. These results indicate that channel activity may be
primarily regulated by cis redox potential and that the
trans potential or the redox potential gradient across the
membranes may have minor effects. This is consistent with previous
observations that GSH inhibited and GSSG stimulated channel activity
when applied to the cytoplasmic, but not the luminal, side of the RyR
(40). Our results also indicate that channel activity
depended on thiol modification on the channel induced by application of
pCMPS/DTT in the cis side of the RyR (Figs. 1 and 2 and see
Ref. 24). Similar activation of the RyR channels has been
reported by oxidation of the cis, but not the
trans, side by exposure to another mercurial water-soluble
oxidant, thimerosal, indicating again that the sulfhydryl (SH) residues
involved in the observed Po changes were only
accessible from the cis side (3, 18).
In addition, the dose-dependent inhibitory effect of DTT (Fig. 4) seems
to be consistent with results from redox potential fixed by a
[GSH]/[GSSG] buffer solution (Fig. 8). Taken together, our results
suggest that cis redox state plays a primary role in
controlling channel activity, irrespective of the use of a
[GSH]/[GSSG] buffer solution or a pCMPS/DTT solution. Our results
are in marked contrast to the recent report by Feng et al.
(10) in which channel activity was primarily determined by
the transmembrane redox potential gradient but not by either the
cis or trans redox potential by itself. The
discrepancy between Feng et al. (10) and results presented
here remains to be resolved. We used purified proteins, whereas they
used SR vesicles. This difference of RyR preparations, however, cannot
be the explanation for the discrepancy, because effects of pCMPS in
the cis side alone on RyR channel activation in SR vesicles
were already reported (21, 24).
Previously, the occurrence of at least two groups of RyR channels with
low and high Po values, when the RyR was
incorporated into planar lipid bilayers, has been reported (10,
18, 21). In this study, we found that the RyR1 channels
consisted of several populations with different
Po (0 
Po 0.5) at
the optimum Ca2+ concentration of 0.1 mM (Table 1). This
indicates that many stepwise states of channel activity may occur in
the RyR channels. pCMPS enhanced activity of the
low-Po channel in a dose-dependent manner (Fig.
4). The effect of pCMPS was reversed by addition of a reducing reagent,
DTT (Fig. 1C and see Ref. 21). Exposure to DTT,
on the other hand, dose-dependently decreased
high-Po channel activity, and subsequent
application of pCMPS increased activity again (Fig. 2), indicating that
pCMPS/DTT may act via the SH residues. In addition, treatment of the
low-Po channel with pCMPS (Fig. 4A)
or addition of DTT to the high-Po channel (Fig.
4B) caused several intermediate states in
Po at the single channel level. These findings
suggest that there are multiple SH residues involved in activation and
inhibition of RyR1 channels and that many stepwise states of channel
activity (as shown in Table 1) may be attributable to
oxidation/reduction states of these multiple SH residues. This is
consistent with the recent finding that RyR1 channel activity
correlates with the redox state (or numbers of SH groups) on the
channel molecule, i.e., oxidation of ~10 thiols had little effect on
channel activity, the loss of 10~25 thiols activated the channel in a
number-dependent manner, and further loss of thiols irreversibly
inactivates the channel (36). The multiple
oxidation/reduction of these reactive SH residues (probably with
different thresholds) may enable subtle regulation of the RyR1 channel
activity by redox potential. For ease of analysis, in this study, we
conveniently classified channels into the following two groups:
high-Po (Po 
0.05 at pCa 4) and low-Po
(Po < 0.05 at pCa 4) channels (Table 1).
This separation was satisfactory to analyze the properties of RyR
channels. The two groups showed obviously distinct behaviors in
response to Ca2+ (Fig. 3) and to modulators of CICR (Fig.
5).
It has been accepted that SH oxidation and reduction modifies RyR
channel activity (i.e., the activity at the optimal Ca2+;
see Refs. 1, 3, 8-10,
21, 25, 31, 35,
40). In addition, Marengo et al. (18)
demonstrated that the Ca2+ dependence also depends on the
redox state of the RyR channel. Donoso et al. (7) recently
found that oxidation of the RyR1 with thimerosal suppressed the
inhibitory effect of Mg2+ on CICR. In this study, we found
that channels in the high-Po state (Fig. 5),
channels activated by exposure to pCMPS (Fig. 6), and channels
activated by setting cis redox potential to 180 mV (Fig.
8) were all stimulated by AMPPCP and/or caffeine, whereas channels with
low Po activity were apparently insensitive to
these drugs (Figs. 5-8). These observations suggest that actions
of adenine nucleotides and caffeine on the RyR1 channel may also depend
on the redox state. Adenine nucleotides increase CICR activity without changing Ca2+ sensitivity. Caffeine sensitizes RyR channels
to Ca2+ for activation and also increases the activity at
the optimum Ca2+ concentrations (for example, caffeine
increased Po of the pCMPS-activated channel at
pCa 5 in Fig. 6B). Thus both drugs have a common positive effect on channel activity, irrespective of the Ca2+
sensitivity. Recently, Xia et al. (39) reported that the
initial rate of ryanodine binding to the RyR vesicles depends on redox potentials in a solution without changing Ca2+ sensitivity;
oxidation increased the initial binding rate, whereas reduction
decreased it (see Fig. 3 in Ref. 39). They suggested that
the magnitude of the channel response may be set by the cellular redox
potential. In addition, they showed that Ca2+,
Mg2+, and caffeine modulate the redox potential of SH
residues involved in activation of the RyR. Therefore, it is reasonable
to assume that the redox potential is a primary factor determining the
maximum channel activity and may alter the effects of CICR modulators. If this assumption is true, then the redox states might greatly modulate the channel-activating action of caffeine or adenine nucleotides. At the present time, however, definite conclusions cannot
be reached, partly because of large variations of
Po. This primary modulating effect of redox
potential may explain why an extreme reduction of the RyR molecule
produced by exposure to DTT or setting redox potential to 231 mV
failed to activate the channel on application of adenine nucleotide or
caffeine (Figs. 5 and 8).
Total GSH (GSH + GSSG) concentration in skeletal muscle has been
estimated to be ~3 mM and GSSG to be ~50 µM (16,
32). Redox potential in the cell cytosol is estimated to be
about 220 to 230 mV, although the intraluminal side of the SR has
been reported to be in an oxidative state (redox potential
approximately 180 mV; see Ref. 10). This means that
cytoplasm of resting muscle cells probably is in a reduced state. In
the present experiment, fixation of the cis potential to
220 mV using a [GSH]/[GSSG] buffer slightly decreased the
Po of the high-Po
channel, but further reduction to 231 mV led to a marked decrease in
Po (Fig. 8). Such low-Po
channels did not respond to AMPPCP. No response of the channels to
AMPPCP was observed when trans redox potential of the
low-Po channel was fixed at 180 mV. Thus, in
resting muscle cells, the CICR activity of the RyR channel may be set
at a lower level by sulfhydryl reduction, even in the presence of high
concentrations of intracellular ATP (~5 mM; see Ref. 19)
and even if the intraluminal side of the SR were in an oxidized state
(10). In contrast, setting the cis potential to
180 mV markedly increased Po of the
low-Po channel and sensitized channels to AMPPCP
(Fig. 8). Therefore, if the redox potential of cytoplasm would become
more oxidized, the activity of the RyR channel would be enhanced.
Repetitive muscle contractions, as occur in strenuous exercise, produce
reactive oxygen species (6, 15, 28, 30, 34) that oxidize
GSH to increase in intracellular GSSG, resulting in a shift of the intracellular redox balance toward an oxidative state. It has been
reported that skeletal muscle dysfunction may occur after intense
exercise (29, 30). The activation of RyR channels through
the shift in the myoplasmic redox potential might also be involved in
the pathophysiological changes of skeletal muscles.
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ACKNOWLEDGEMENTS |
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This work was supported by Grants-in-aid for Scientific Research 09470013 and 1267044 (to T. Oba) from the Japan Society for the Promotion of Science.
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FOOTNOTES |
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Address for reprint requests and other correspondence: T. Oba, Dept. of Physiology, Nagoya City Univ. Medical School, Mizuho-ku, Nagoya 467-8601, Japan (E-mail: tooba{at}med.nagoya-cu.ac.jp).
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.
10.1152/ajpcell.01273.2000
Received 17 October 2000; accepted in final form 22 October 2001.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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), high-Po (
),
pCMPS-treated low-Po (
), and
DTT-treated high-Po (
) channels.
Numbers represent the no. of determinations. Data are means ± SD.
pCa-Po relationships for
high-Po channels and pCMPS-activated
low-Po channels appeared to be similar, although
the latter channels were inhibited less at high Ca2+
concentrations. Low-Po channels and DTT-treated
high-Po channels, in contrast, showed unclear
Ca2+ dependence.
, High-Po
channel activity; 
, low-Po
channel activity; 
, low-Po
channels activated in the presence of 10 µM pCMPS; 
,
high-Po channels inhibited by 30-100 µM
DTT. 
P < 0.05 and 