First Department of Internal Medicine, Faculty of Medicine, Kagoshima University, Kagoshima 890-8520, Japan
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ABSTRACT |
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With inside-out patch recordings in ventricular myocytes from the hearts of guinea pigs, we studied ATP-sensitive K+ (KATP) channels activated by phosphatidylinositol 4,5-bisphosphate (PIP2) with respect to sensitivity to ATP when in either a rundown state (RS) or a non-rundown state (NRS). Rundown of KATP channels was induced by exposure either to ATP-free solution or to ATP-free solution containing 19 µM Ca2+. Exposure of membrane patches to 10 µM PIP2 reactivated channels with both types of rundown. The reactivation by PIP2 did not require ATP in the bath. The IC50 of channels recovered from RS and before the rundown was 37.1 and 31.1 µM, respectively. PIP2 irreversibly increased the mean current when the channel was in the NRS. This was associated with a shift of IC50 to 250.6 µM after PIP2 exposure. PIP2 activates NRS KATP channels by decreasing their sensitivity to ATP, whereas PIP2 reactivates RS-KATP channels independently of ATP without changing ATP sensitivity.
channel rundown; ventricular myocytes
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INTRODUCTION |
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ATP-SENSITIVE
K+ (KATP) channels
participate importantly in the physiology and pathophysiology of
various tissues such as cardiac muscle cells, pancreatic -cells,
skeletal muscle cells, smooth muscle cells, and cells of the
ventromedial hypothalamic nucleus (1, 2, 18, 28). In the
heart, the KATP channel has been implicated in action
potential shortening during ischemia and may have a cardioprotective
role in severe ischemic events (20, 34, 36). The opening
probability of the KATP channel is substantially decreased
by micromolar intracellular concentrations of ATP, which is now known
to be a channel regulator in addition to functioning as a carrier of
energy and a promoter of chemical reactions within the cell
(20). The channel inhibition does not occur via
phosphorylation of the channel protein, because a nonhydrolyzable
analog of ATP inhibits KATP channel activity (1, 2,
20). KATP channel activity gradually decreases when
the integrity of the cell is disrupted by excising a patch membrane
(rundown phenomenon). Thus maintenance of the KATP channel
activity also may depend on another regulatory process that may involve
soluble elements as yet unidentified.
At the cellular level, phospholipids and their metabolites in the membrane have been shown to be essential in the regulation of cell functions. In addition to serving as important structural components of cell membranes, phospholipids generate signaling molecules that transduce the action of hormones or transmitters interacting with cell surface receptors to cytoplasmic effectors. Recently, a novel role of membrane phospholipids has been described concerning regulation of KATP channel activity: this has been reviewed by Hilgemann (10). Phosphatidylinositol 4,5-bisphosphate (PIP2) is a phospholipid that has been reported to maintain activity of KATP channels (11) undergoing Ca2+-induced rundown (5). Recent experiments have demonstrated that wortmannin blocked MgATP-dependent recovery of activity of channels reconstituted with Kir6.2/sulfonylurea (SUR)-2A, subunits of KATP channels, that ran down in a Ca2+-containing solution (33). Because exposure to PIP2 produced recovery of the rundown channels even in the presence of wortmannin, membrane lipid phosphorylation and production of PIP2 or phosphatidylinositol 3,4,5-trisphosphate appear to be principal regulators of rundown KATP channels (33). The effectiveness of anionic phospholipids, such as phosphatidylinositol 4-monophosphate and PIP2, in activating KATP channels has been found to be proportional to the number of negative charges on the head group of the phospholipid (4). PIP2 reduces the ATP sensitivity of the channel (3, 24). These findings suggest that PIP2 may determine ATP sensitivity of the channel by modulating ATP binding to positively charged amino acids in the COOH-terminal portion of Kir6.2, where ATP binding reportedly closes the channel (30). However, whether KATP channels reactivated from the rundown state (RS) by PIP2 had decreased sensitivity to ATP remains unclear. In the present work, we studied the effects of PIP2 on KATP channels in either an RS or a non-RS (NRS) with respect to changes in ATP sensitivity.
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METHODS |
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Isolation of single ventricular myocytes. Single ventricular myocytes were isolated from the hearts of guinea pigs (200-300 g) as previously described (27). Briefly, the animals were anesthetized by an intraperitoneal injection of pentobarbital sodium (25 mg/kg) and artificially ventilated. The chest was opened, the aorta was cannulated, and the coronary arteries were perfused with Tyrode solution. The heart then was removed, suspended on a Langendorff apparatus, and perfused with Tyrode solution containing (in mM): 136.9 NaCl, 5.4 KCl, 1.8 CaCl2, 0.5 MgCl2, 0.33 NaH2PO4, 5.5 glucose, and 5.0 HEPES-NaOH (pH 7.4). The perfusate was changed to nominally Ca2+-free Tyrode solution (100 ml) and a digestion solution containing 0.04% type II collagenase (Worthington) for 10 min. To wash out collagenase, the heart was perfused with 100 ml of Kraftbrühe (K-B) solution (12) containing (in mM): 40 KCl, 20 taurine, 50 glutamic acid, 20 KH2PO4, 3.0 MgCl2, 0.5 EGTA, 10 glucose, and 10 HEPES-KOH (pH 7.4). The left ventricle was removed and cut into small pieces (5 mm2) in K-B solution and dispersed mechanically into single cells. The dispersed myocytes were maintained in K-B solution at 4°C for at least 1 h before use. Next, single ventricular myocytes were placed in a recording chamber (500 µl) that was filled with Tyrode solution; the solution then was changed to the standard internal solution containing (in mM): 134.5 KCl, 0.5 KH2PO4, 2.0 MgCl2, 1.0 EGTA, and 5.0 HEPES-KOH (pH 7.2). The final K+ concentration of this solution was 140 mM, and the free Ca2+ concentration was calculated to be <0.1 nM. To evoke Ca2+-induced channel rundown, 1 mM CaCl2 was added to this solution resulting in a free Ca2+ concentration of 19 µM as calculated using the Chelator software package provided by van Heeswijk et al. (32). The Mg2+-free internal solution was nominally free of Mg2+ and contained 1 mM EDTA rather than equimolar EGTA [other constituents (in mM): 5 HEPES, 0.5 KH2PO4, and 134.5 KCl]. The pH was adjusted to 7.2 with KOH; the free Mg2+ concentration was <1 nM. ATP was added to these internal solutions as required.
Single-channel current recordings.
Standard patch-clamp techniques (9) were used to record
single KATP channel currents from inside-out membrane
patches. Patch pipettes were pulled from hard glass tubing (Sutter
Instruments), coated with silicon resin to reduce their electrical
capacitance, and fire-polished immediately before use. The composition
of the pipette solution was as follows (in mM): 140 KCl, 2.0 CaCl2, and 5.0 HEPES-NaOH (pH 7.4). The pipettes had
resistances between 5 and 10 M when filled with this solution. After
the G
seal had been established on a cell exposed to standard
internal solution containing 0.3 mM ATP, the patch membrane was
excised. The patch membrane potential was held at
60 mV.
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Chemicals and conditions.
ATP-2Na, PIP2, and adenosine
5'-O-(3-thiotriphosphate) (ATPS) were purchased from
Boehringer (Mannheim, Germany). PIP2 was dissolved in DMSO
(0.1%) diluted in the internal solution containing required ATP
concentration by sonication on ice for 30 min. Stimulatory effects of
PIP2 on activity of KATP channels seemed to be
reduced ~5 h after newly making PIP2-containing solution.
In that case, we prepared a new PIP2-containing solution
every 4 h throughout the experiments. Glibenclamide was
purchased from Sigma (St. Louis, MO). All experiments were performed at
room temperature (22-25°C).
Statistical analysis. All data are expressed as means ± SE from the number of membrane patches. Data were analyzed with Wilcoxon's signed-rank test or Mann-Whitney's U test, with P < 0.05 accepted as statistically significant.
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RESULTS |
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Effect of PIP2 on rundown KATP channels.
A rundown state of the KATP channel (RS channel) was
induced by superfusion with ATP-free solution containing either free Ca2+ concentrations <1 nM (spontaneous rundown) or 19 µM
Ca2+ (Ca2+-induced rundown; Fig.
1, A and B).
Activity of the KATP channel current, which was fully
activated at initiation of recording without ATP, decreased with time
during subsequent exposure of the membrane patch to the ATP-free
solution (Fig. 1A). The time course of the channel rundown
process in ATP-free solution varied among the membrane patches tested.
In general, rundown of the channel was attained with ~7.6 ± 3.5 min (n = 10) of exposure to the ATP-free solution (when
the rundown is defined by 90% reduction of the channel current levels
in control). When rundown of the channel was studied with the membrane
patch exposed to a high-Ca2+ concentration (Fig.
1B), rundown occurred much more rapidly than in the
spontaneous rundown observed under low-Ca2+ concentration
(Fig. 1, B vs. A). In membrane patches exposed to
19 µM Ca2+, we observed rundown of the channel activity
within 20 s (n = 22). In both situations, exposure
of the patch membrane to PIP2 (10 µM) slowly reactivated
the KATP channel. The current reactivated by
PIP2 was a result of KATP channel opening,
because intermittent exposure to various concentrations of ATP dose
dependently inhibited the channel, and single-channel unitary currents
were identical to those observed in the control (Fig. 1B,
see also inset). Dose-response relationships between channel
activity and ATP concentrations before the rundown and after
reactivation of channels by PIP2 were plotted (Fig.
1C). In these experiments, we used 19 µM Ca2+
exposure for 20-60 s to produce the channel rundown and
subsequently superfused 10 µM PIP2 and 0 mM ATP solution
intermittently for 1 min each to reactivate the channel. ATP
concentration-dependent inhibition of the channel then was examined
using the protocol illustrated in Fig. 1B. Once recovery of
channel activity was established after exposure to PIP2,
the channel openings were maintained after washout of PIP2.
The IC50 of control and reactivated channels after
Ca2+-induced rundown were 31.1 and 37.1 µM, respectively
(n = 5). Reactivation of RS channels by
PIP2 did not require the presence of ATP in the bathing
solution (Fig. 1A).
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Effect of PIP2 on non-rundown KATP
channels.
PIP2 activated the NRS KATP channels
regardless of the presence of ATP. Figure
3A depicts current tracings
recorded in the presence of 0.3 mM ATP showing activation of channels
by exposure to 10 µM PIP2. Subsequent exposure to 3 mM
ATP reduced channel activity that was greater than that at 0.3 mM ATP
before PIP2 treatment. Thus loss of sensitivity of channels
to ATP after PIP2 treatment was suggested. Because
glibenclamide, a specific KATP channel blocker, inhibited
the channels, the activation of channels observed involved opening of
KATP channels. The blocking efficacy by 10 µM
glibenclamide of the activity of the channels was 83.1 ± 8.0%
(n = 5, P < 0.02) compared with 100%
inhibition attainment without PIP2 treatment.
Single-channel conductance under control conditions and after
PIP2 treatment did not change. The slope conductance was
83.3 pS both under control conditions and with PIP2
treatment (data not shown). Mean open and closed times for the channels
in the burstlike openings were, respectively, 2.11 ± 0.02 (n = 5) and 0.27 ± 0.02 ms (n = 5) under control conditions and 2.33 ± 0.02 (n = 5) and 0.23 ± 0.03 ms (n = 5) with
PIP2 exposure when they were analyzed in open- and
closed-time histograms. Thus kinetic properties during burstlike
openings were not influenced by PIP2. These results
indicated that PIP2 increased burst durations and reduced
interburst intervals of channels and consequently increased opening
probability in association with decreasing glibenclamide sensitivity.
Dose-response relationships of channel inhibition with ATP before and
after PIP2 treatment are presented in Fig. 3B.
The curves fit IC50 of 31.1 µM under control conditions
and 250.6 µM after exposure to PIP2. Thus activation of
channels by PIP2 was due to reduction of the ATP
sensitivity in the case of the NRS channel. The KATP
channel was fully activated by decreasing the ATP concentration from
0.3 to 0 mM ATP (Fig. 4A),
indicating that the channel was not run down in this state. Of course,
subsequent application of PIP2 no longer increased the
channel activity, and repetitive exposure to various concentrations of
ATP resulted in reduction of sensitivity to ATP (Fig. 4A,
bottom). Thus exogenously applied PIP2 may be
kept in the lipid membrane to some extent even after washout and
decreases the ATP sensitivity of NRS channels. SUR receptors have a
domain where MgATP binds and is hydrolyzed (31). It has
been reported that addition of MgATP in the presence of SUR led to an
increase in ADP concentration by the hydrolysis (8). These
results may suggest a mechanistic possibility for PIP2-induced reduction of ATP sensitivity of the channel
that PIP2 might increase the rate of hydrolysis of MgATP at
SUR. PIP2 activated the channel in the presence of 0.3 mM
ATPS, a nonhydrolyzable analog of ATP (Fig. 4B),
indicating that reduction of ATP sensitivity by PIP2 did
not involve hydrolysis of ATP. This was further confirmed in following
experiments. After the ATP sensitivity of the channel was tested in the
presence of Mg2+, Mg2+ was removed in the
presence of 0.3 mM ATP. Channel opening at 0.3 mM ATP was increased by
reducing Mg2+, and the channel was fully activated by 10 µM PIP2. Subsequent exposure to various concentrations of
MgATP revealed decreased sensitivity of the channel to ATP (Fig.
4C). These results suggest that PIP2-induced
reduction of ATP sensitivity did not depend on the presence of MgATP.
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DISCUSSION |
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In the present study, we demonstrated that PIP2 reactivated KATP channels after channel activity ran down in ATP-free bathing solution with high concentrations of Ca2+. ATP sensitivity of the reactivated channel was not changed compared with that of control. On the other hand, NRS KATP channels were similarly activated by PIP2 in association with much lower sensitivity to ATP. Thus PIP2 may influence gating of channels by mechanisms that differ for RS and NRS channels.
The time course of rundown of channel activity in the presence of 19 µM Ca2+ (Ca2+-induced rundown) was more rapid
than that induced in ATP-free solution with low-Ca2+
concentration (spontaneous rundown). PIP2 reactivated both
types of rundown channel (3, 4, 24, 33). After treatment
of membrane patches with 10 µM PIP2 for 5 min, the time
course of rundown during exposure to Ca2+ was slower than
that seen before PIP2 treatment (Fig. 2). Thus we speculate
that Ca2+ and PIP2 either allosterically
interact to regulate channel activity, or both elements may compete at
the same site. Recovery from spontaneous rundown of the
KATP channel is known to occur after exposure to an
MgATP-containing solution (21, 26). Because MgATP, but neither a nonhydrolyzable analog of ATP nor ATP4, can
mimic this phenomenon, a phosphorylation mechanism has been suspected
(18, 21). However, a recent study demonstrated this MgATP-dependent reactivation of the channel to be mimicked by PIP2 in the absence of ATP, and MgATP-induced reactivation
was prevented by an inhibitor of phosphatidylinositol 3- and 4-kinases, wortmannin (33). Thus lipid phosphorylation may be a
principal mechanism for the reactivation of the rundown channel, as
opposed to reactivation by protein phosphorylation involving the
channel per se or related elements. Spontaneous or
Ca2+-induced rundown of the channel may be due to
deficiency of PIP2 in the membrane. Depolymerization of
actin filaments (F actin) may be involved in the mechanism for
KATP-channel rundown. F actin is disrupted when
actin-binding proteins are activated by elevated cytosolic
Ca2+ concentrations (19). Depolymerized actin
(G actin) may not be able to maintain high opening probability of the
channel in ATP-free solution (5). Furukawa et al.
(5) have reported that actin-depolymerizing agents such as
cytochalasins B and D or DNase I enhanced the rate of rundown of the
KATP channel. In contrast, these authors found that
phalloidin, an actin-filament stabilizer, as well as PIP2
prevented rundown of the channel. These results suggest that the
channel is regulated by the actin system. Ca2+ activates
actin-binding proteins that sever and cap F actin, and disruption of
the network readily results (13). PIP2 has been reported to inhibit the activity of Ca2+-sensitive F
actin-severing proteins (14, 17, 19, 25) and to remove
these actin-binding proteins from the barbed ends of depolymerized F
actin. Thus the presence of PIP2 may foster repolymerization of G actin.
Rundown may be enhanced by dissolution of PIP2 mediated by endogeneous Ca2+-dependent phospholipase C (33). Actin filament disrupters reportedly can attenuate ATP-dependent inhibitory gating of KATP channels (29, 35). The hypothesis that Ca2+-dependent depolymerization and PIP2-induced repolymerization of the actin filament network in the submembrane region may be a major mechanism underlying both KATP channel rundown and reactivation remains to be tested.
Fan and Makielski (4) have postulated an electrostatic interaction between the anionic head groups of PIP2 and the positively charged amino acid residues of the COOH terminus of Kir6.2 to explain channel activation by PIP2 associated with a shift of ATP sensitivity. Similar findings demonstrating that PIP2 reduced the ATP sensitivity of the channel have been reported consistently (3, 24). SUR has been suggested to have a domain of ATPase activity, and hydrolysis of ATP is needed to transmit the signaling of binding of potassium channel openers to pore subunits, Kir6.2, to open the channel (22, 31). When 1-3 mM ATP and membranes including SUR were present, ADP at the end of incubation was increased by 5-15 times ranging from 58 to 92 µM (8). Thus ATP hydrolysis at submembrane may produce micromolar levels of MgADP, and this concentration may be high enough to increase the activity of KATP channels because MgADP is a KATP channel stimulator (6, 15, 36). Whether these phenomena occur at a site close to channels and are involved in PIP2-induced loss of ATP sensitivity in KATP channels were tested in Fig. 4, B and C. Activation of the channel by PIP2 associated with decreased ATP sensitivity did not require the presence of MgATP or Mg2+. Thus hydrolysis of ATP is not involved in PIP2-induced reduction of ATP sensitivity. An expression of mutant phosphatidylinositol-4-phosphate 5-kinase (PIP5K), inactive form, did not influence the IC50 of wild-type KATP channels, whereas it increased ATP sensitivity of a mutant KATP channel that has lower ATP sensitivity (23). PIP5K may regulate the PIP2 concentration in the membrane and determine the ATP sensitivity of the channel. The findings that PIP2 did not lower the ATP sensitivity of the channel reactivated from the rundown state but lowered NRS channels suggest that an unidentified element distal to PIP2 may be involved in the PIP2-induced modification of the ATP sensitivity, and this may be lost in rundown process of the channel.
High affinity of tolbutamide for channel inhibition was reportedly impaired when the membrane patches were treated with PIP2 (16). We used 10 µM glibenclamide to test whether the channel openings stimulated by PIP2 were those of KATP channels (Fig. 3). Although the channel has sensitivity to glibenclamide, the channel was not closed completely even at 10 µM glibenclamide. The blocking efficacy of 10 µM glibenclamide on KATP channel after PIP2 treatment was 83.1 ± 8.0% (n = 5) compared with 100% inhibition for the channels without treatment of PIP2. It has been suggested that glibenclamide binds to the channels with high- and low-affinity sites (7). Low-affinity binding of glibenclamide might be impaired after PIP2 treatment. This hypothesis remains elucidated.
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ACKNOWLEDGEMENTS |
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This work was supported in part by a grant-in-aid for Scientific Research from the Ministry of Education, Science, and Culture of Japan (to M. Kakei).
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FOOTNOTES |
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Address for reprint requests and other correspondence: M. Kakei, First Dept. of Internal Medicine, Faculty of Medicine, Kagoshima Univ., 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan (E-mail: mkakei{at}med4.kufm.kagoshima-u.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.
Received 2 February 2000; accepted in final form 18 September 2000.
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