Division of Perinatal Medicine, Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut 06510
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ABSTRACT |
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Several lung
surfactant secretagogues are known to activate protein kinase C (PKC)
in type II cells. Such agents include
12-O-tetradecanoylphorbol 13-acetate
(TPA) and cell-permeable diacylglycerols that directly activate PKC.
Other agents include ATP and UTP, which act at
P2Y2 receptors coupled to
phosphoinositide-specific phospholipase C, activation of which leads to
formation of diacylglycerols and consequent activation of PKC.
Activation of PKC is associated with redistribution of enzyme from a
cytosolic to a membrane fraction of the cell. We examined the PKC
isomers that are translocated by ATP, UTP, TPA, and dioctanoylglycerol
in cultured type II cells isolated from adult rats. PKC isoforms were
identified by Western blotting using isoform-specific antibodies.
Treatment of type II cells with ATP, UTP, TPA, and dioctanoylglycerol
resulted in a significant redistribution of PKC-µ from cytosol to
membrane. TPA and dioctanoylglycerol also activated PKC-, -
I,
-
II, -
, and -
, but those isoforms were not activated by ATP or
UTP. The effects of TPA and dioctanoylglycerol on PKC-µ were more
pronounced than those of the P2Y2
agonists, and the effect of TPA was also more rapid than that of ATP.
The data show that direct activators and agents that generate
endogenous diacylglycerols have different PKC activation patterns.
Because it is activated by different types of secretagogues, PKC-µ
may have an important role in the physiological regulation of
surfactant secretion.
P2Y2-receptor agonists; pulmonary surfactant; 12-O-tetradecanoylphorbol 13-acetate; dioctanoylglycerol; translocation
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INTRODUCTION |
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THERE IS EVIDENCE THAT protein kinase C (PKC) has an important role in the regulation of surfactant secretion (23, 24). Agonists that activate PKC are among the most effective surfactant secretagogues in isolated type II cells (23). Such agents include 12-O-tetradecanoylphorbol 13-acetate (TPA) and the cell-permeable diacylglycerols dioctanoylglycerol and 1-oleoyl-2-acetylglycerol, which directly activate PKC upon uptake by the cell. Secretagogues that activate PKC indirectly include the P2Y2-receptor agonists ATP and UTP (10). The P2Y2 receptor is coupled to activation of phosphoinositide-specific phospholipase C (PLC) via the GTP-binding protein Gq (23). Activation of PLC results in the hydrolysis of phosphatidylinositol bisphosphate and generation of diacylglycerols and inositol trisphosphate (17). Such intracellular diacylglycerols can then activate PKC. PLC activation (12, 21, 30) and increased PKC activity (3, 21) in response to ATP have been reported in type II cells.
Eleven PKC isoforms are currently known to exist (17, 20). They include
the Ca2+-dependent conventional
,
I,
II, and
isoforms as well as the novel
,
,
,
and
isoforms and atypical
,
, and µ isoforms that do not
require Ca2+ for activation (20).
The
,
I,
II,
,
,
,
, and µ PKC isoforms have
been identified in the type II cell (11, 16), and TPA was reported to
activate PKC-
, PKC-
, PKC-
, and PKC-
but not PKC-
(16).
There are currently no published data on the identity of the PKC
isoforms that are activated by
P2Y2 agonists or by cell-permeable
diacylglycerols in the type II cell. The goal of the present study was
to identify the PKC isoforms that are activated by ATP, UTP, and
dioctanoylglycerol in type II cells.
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MATERIALS AND METHODS |
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Chemicals and reagents. Porcine pancreatic elastase was obtained from Elastin Products (Owensville, MO), FCS was from Hyclone (Logan, UT), rat IgG was from Accurate (Westbury, NY), isoform-specific rabbit polyclonal PKC antibodies were from Santa Cruz Biotechnology (Santa Cruz, CA), horseradish peroxidase-conjugated goat anti-rabbit IgG was from Sigma (St. Louis, MO), and Western Blot Chemiluminescence Reagent was from DuPont-New England Nuclear (Boston, MA). ATP and UTP (sodium salts), TPA, 1,2-dioctanoyl-sn-glycerol, and 5'-(N-ethylcarboxyamido)adenosine (NECA) were obtained from Sigma; terbutaline sulfate (Brethine) was from Geigy Pharmaceuticals (West Caldwell, NJ), and ionomycin was from Calbiochem (San Diego, CA). TPA, dioctanoylglycerol, and ionomycin were dissolved in DMSO. The final concentration of DMSO in the culture medium was 0.5%, and this amount was also included in the corresponding controls. DMSO has no effect on phosphatidylcholine secretion in type II cells (9).
Type II cell isolation and culture. In each experiment, type II cells were isolated from the pooled lungs of six adult male Sprague-Dawley rats as described previously (8). The isolation method involves digestion of the blood-free lungs with elastase and separation of type II cells from contaminating cells by panning on bacteriological dishes coated with IgG (4). The freshly isolated cells were cultured on plastic dishes in DMEM containing 10% FCS, streptomycin (100 µg/ml), penicillin (100 U/ml), gentamicin (10 µg/ml), and amphotericin B (2.5 µg/ml) for 18-20 h in 90% air-10% CO2 at 37°C. We previously reported that >95% of the attached cells were identifiable as type II pneumocytes at that stage (8).
Treatment with surfactant secretagogues. After overnight culture, the medium was removed, and the type II cell monolayers were washed with fresh DMEM without FCS or antibiotics. Fresh DMEM was then added, and the cells were returned to the incubator. After 30 min of preincubation in the fresh medium, agonists or solvent vehicle was added, and the incubation was continued for 5 min except in time-course experiments when the period of incubation varied from 1 to 10 min. The agonist concentrations used were those previously shown to optimally stimulate phosphatidylcholine secretion and to be nontoxic in type II cells (6-8, 10).
Subcellular fractionation. The medium was removed, homogenization buffer consisting of 20 mM Tris · HCl (pH 7.5), 250 mM sucrose, 1 mM EDTA, 1 mM EGTA, 1 mM dithiothreitol, 1 mM phenylmethylsulfonyl fluoride, 10 µg/ml aprotinin, 1 µg/ml pepstatin, 10 µg/ml leupeptin, and 10 µg/ml phosphoramidon was added, and the cells were scraped off the dishes with a rubber policeman and further disrupted by sonication. The sonicate was centrifuged at 800 g for 10 min, and the resulting supernatant was fractionated into cytosolic and membrane fractions by centrifugation at 100,000 g for 45 min. The cytosolic fraction was concentrated to ~10% of its volume using Centricon concentrator tubes (Amicon, Beverly, MA), after which the buffer was adjusted to its original concentration. The membrane pellet was extracted with homogenization buffer containing 1% Triton X-100 for 1.5 h at 4°C with rigorous vortexing. The extract was centrifuged at 100,000 g for 30 min, and the supernatant was used for subsequent analysis.
Western blotting. PKC isomers were analyzed by Western blotting as described previously (11). Proteins (20-30 µg) were separated by SDS-PAGE under denaturing conditions (15) on Tris-glycine Ready Gels (Bio-Rad, Hercules, CA) consisting of a 7.5% resolving gel with a 4% stacking gel overlay. Resolved proteins were transferred to polyvinylidene difluoride membranes (0.2 µm) that were subsequently incubated in methanol for 20 min, washed with 20 mM Tris buffer containing 0.05% Tween 20 and 150 mM NaCl (Tris- and Tween-buffered saline, TTBS), and incubated for 2 h in TTBS containing 5% nonfat dry milk. The membranes were then sequentially incubated in TTBS containing 4% nonfat dry milk with the primary antibody (1:100 dilution) for 1 h, peroxidase-conjugated goat anti-rabbit IgG (1:15,000 dilution) for 1 h, and the chemiluminescence reagent for up to 1 min. The blots were exposed to X-ray film (Hyperfilm MP; Amersham, Arlington Heights, IL), and the autoradiographs were quantitated by scanning densitometry (Personal Densitometer SI and Image QUANT software; Molecular Dynamics, Sunnyvale, CA). Each protein was analyzed on one to two Western blots with two to three different exposures of each, and the data were meaned to yield a single value. Some blots were stripped and reprobed (11) with a different antibody. As previously reported, data from fresh and stripped blots were the same (11).
Other. Protein was measured by a Coomassie blue binding method using an assay kit supplied by Bio-Rad.
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RESULTS |
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Activation of PKCs is accompanied by a redistribution of the enzyme
from the cytosol to the membrane fraction of the cell (20). We
therefore examined the effect of the
P2Y2 agonists ATP and UTP and the
direct PKC activators TPA and dioctanoylglycerol on the distribution of
selected PKC isomers between the cytosolic and membrane fractions of
type II cells. We focused on the ,
I,
II,
, µ,
, and
isomers of PKC because we previously found that those are all
expressed in the type II cell (11). We did not examine the
,
,
, and
isomers because PKC-
is only weakly expressed, and PKCs
,
, and
are not expressed at all in the type II cell (11).
The effects of surfactant secretagogues on the amounts of PKC isomers
in the cytosolic and membrane fractions of type II cells are shown in
Fig. 1. ATP, UTP, TPA, and
dioctanoylglycerol decreased the amount of PKC-µ in the cytosol and
produced a corresponding increase in its amount in the membrane
fraction. The effects of TPA and dioctanoylglycerol were more
pronounced than those of ATP and UTP. As shown in Table
1, the amount of PKC-µ in the cytosol was
decreased 80-90% by TPA and dioctanoylglycerol and 40-50%
by ATP and UTP. Similarly, the amount of PKC-µ in the membrane fraction was increased 12-fold by TPA, 8-fold by dioctanoylglycerol, and 2.5-fold by ATP and UTP (Table 2).
These redistribution data show that PKC-µ is activated by all four
surfactant secretagogues and that the extent of activation is greater
in response to TPA and dioctanoylglycerol than to the
P2Y2 agonists.
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The time course of the changes in PKC-µ redistribution in response to
TPA and ATP is shown in Fig. 2. TPA caused
a rapid redistribution that was complete in 1 min, with no further
change up to 10 min. The effect of ATP was slower, with the maximum
effect being apparent 5 min after addition of the agonist. Thus the
time courses of the responses to TPA and ATP are different.
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The ,
I,
II,
, and
PKC isomers were also activated by
TPA and dioctanoylglycerol but not by ATP or UTP. As shown in Fig. 1,
the amounts of those isomers were decreased in the cytosolic fraction
and correspondingly increased in the membrane fraction in response to
TPA and dioctanoylglycerol. The amounts of PKC-
, PKC-
I,
PKC-
II, and PKC-
in the cytosol were decreased as much as 90% in
response to TPA and dioctanoylglycerol, whereas the amounts in the
membrane fraction were increased approximately three- to sevenfold
(Fig. 3). The amount of PKC-
in the
cytosol was decreased ~40%, whereas that in the membrane fraction
was increased two- to threefold by the same agonists (Fig. 3). As in
the case of PKC-µ, TPA also rapidly activated PKC-
, -
I, -
II, -
, and -
(data not shown), and those isomers were not activated by ATP at any time point from 1 to 10 min. PKC-
was not activated by
any of the surfactant secretagogues examined; its distribution between
the cytosolic and membrane fractions was not altered (Figs. 1 and 3).
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The failure of the P2Y2 agonists
to activate more than one PKC was surprising. It has been reported that
the concentration of Ca2+ in the
fractionation buffer can influence the apparent distribution of PKCs
between cytosolic and membrane fractions (20). We therefore varied the
concentrations of EDTA and EGTA in the fractionation buffer. However,
there was no difference in the distribution of any PKC isoform when the
concentrations of EDTA and EGTA were varied from 0.5 to 10 mM and 0.5 to 5.0 mM, respectively. The failure of ATP and UTP to activate
PKC-, -
I, -
II, -
, and -
, therefore, does not appear to
be an artifact of the experimental procedure.
In addition to activating a P2Y2
receptor, ATP is also known to activate an unidentified receptor
coupled to adenylate cyclase on the type II cell (23, 24). We therefore
examined PKC-µ activation in response to surfactant secretagogues
that activate adenylate cyclase-coupled receptors: the adenosine
A2B-receptor agonist NECA and the
-adrenergic agonist terbutaline (23). As shown in Fig.
4, neither terbutaline nor NECA altered the
distribution of PKC-µ between the cytosolic and membrane fractions of
the type II cell. Ionomycin, an ionophore that stimulates surfactant
secretion by increasing Ca2+
uptake (23), also did not activate PKC-µ (Fig. 4). The finding that
it is activated by UTP, an agonist that does not activate an adenylate
cyclase-coupled receptor (10, 23), as well as by ATP but not by other
surfactant secretagogues suggests that activation of PKC-µ by
P2Y2-receptor agonists is an event
that is downstream of
P2Y2-receptor activation.
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DISCUSSION |
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Secretion of surfactant phospholipids is a regulated process that is influenced by several physiological and pharmacological agents (23). At least three signal transduction mechanisms are known to regulate surfactant secretion: activation of receptors coupled to adenylate cyclase with generation of cAMP and ultimate activation of protein kinase A, increased intracellular Ca2+ levels with activation of a Ca2+/calmodulin-dependent protein kinase, and direct or indirect activation of PKC (23, 24). Surfactant secretagogues whose effects are mediated by PKC activation include agents that directly activate the enzyme upon uptake by the cell as well as agents that act at receptors that are ultimately coupled to PKC activation. P2Y2-receptor agonists are in the latter group. The P2Y2 receptor is coupled to PLC, and activation of that enzyme results in the formation of diacylglycerols that then activate PKC (23). The P2Y2-receptor agonists ATP (5, 10, 12, 21, 26) and UTP (10) are known to stimulate diacylglycerol formation in the type II cell, and ATP has also been reported to activate PKC (3, 21). Other surfactant secretagogues reported to activate PLC and PKC in the type II cell include high- and low-density lipoproteins (29), and there is also evidence that vasopressin (2), endothelin-1 (27), and gastrin-releasing peptide (1) act via that signaling mechanism. Such data suggest an important role for PKC in the regulation of surfactant secretion.
PKC is a family of serine/threonine kinases (14). Eleven PKC isomers
are currently known (17). PKC-, -
I, -
II, -
, -
, -µ, and
-
are all present in cultured rat type II cells (11, 16). PKC-
was reported to be weakly detectable in the type II cell in one study
(11) but undetectable and not expressed in another (16). PKC-
, -
,
and -
are not detectable in type II cells (11, 16), although
PKC-
, but not PKC-
or PKC-
, is present in lung tissue (11).
Our data show that PKC-µ is activated by ATP, UTP, TPA, and
dioctanoylglycerol as determined by translocation of enzyme from the
cytosolic to the membrane fraction. PKC-, -
I, -
II, -
, and
-
are also activated by TPA and dioctanoylglycerol but not by the
P2Y2 agonists. The effects of the
direct PKC activators TPA and dioctanoylglycerol and agents that
generate formation of endogenous diacylglycerols are therefore
different. Because ATP and TPA are among the most effective surfactant
secretagogues (22, 23), we were surprised by the finding that ATP
activates only one PKC isomer, whereas TPA activates several. However,
it has been reported that, in other systems, TPA also promotes
redistribution of several PKC isomers, whereas natural agonists
translocate relatively few (20). Whether translocation of PKC-
,
-
I, -
II, -
, and -
in type II cells is of physiological
relevance is a question that needs to be answered.
The extent and time course of PKC-µ activation by the
P2Y2 agonists are also different
from those of TPA and dioctanoylglycerol. In the same experiments, TPA
and dioctanoylglycerol activated PKC-µ to a greater extent than did
ATP and UTP. In these experiments, we used relatively high
concentrations of ATP and UTP, so the differences are unlikely to be
due to insufficient agonist concentrations. TPA also activates PKC-µ
more rapidly than ATP. The time-course difference could be due to the
fact that TPA directly activates PKC, whereas the effect of ATP is
mediated by binding to a receptor and activation of a signal
transduction pathway. However, variable rates of activation of PKCs in
other systems in response to receptor agonists have been reported. Thus
translocation of PKC- to the membrane fraction was apparent 15 s
after addition of thrombin to fibroblasts but not until 15 min after
addition of platelet-derived growth factor (13).
Differences between ATP and TPA in the extent of PKC activation in type II cells have been reported previously. In studies in which PKC activity was measured by phosphorylation of histone, ATP was reported to translocate 17% of total PKC activity from the cytosol to the membrane fraction (3), whereas TPA was reported to translocate two times as much [33% of the total in one study (31) and 40% in another (25)]. Although the activity and Western data cannot be quantitatively compared, nevertheless, both approaches show that TPA is more effective than ATP in activating PKC in type II cells. Activity measurements suggested that ATP translocates both Ca2+-dependent and Ca2+-independent PKCs (3). However, our data show that ATP only activates PKC-µ, a Ca2+-independent isomer (20). Further studies are needed to resolve these conflicting data.
Linke et al. (16) previously reported that the ,
,
, and
isomers of PKC are activated by TPA in the type II cell. In that study,
the
I and
II isomers were not distinguished, and PKC-µ was not
examined (16). PKC-
was not activated by TPA in the study of Linke
et al. (16) or by either TPA, dioctanoylglycerol, or
P2Y2 agonists in the current
study. It has previously been reported that PKC-
is also not
activated by either TPA (13, 18, 19, 28) or diacylglycerols (13) in
other systems. Effects of cell-permeable diacylglycerols on activation
of PKC isomers in type II cells have not been reported previously.
However, it was reported that 1-oleoyl-2-acetylglycerol did not promote translocation of total PKC activity in type II cells (25). That is a
puzzling finding because both 1-oleoyl-2-acetylglycerol and dioctanoylglycerol are equally effective surfactant secretagogues (22).
ATP stimulates surfactant secretion to a greater extent than UTP (9, 10). That is likely due to the fact that ATP activates both a P2Y2 receptor and a receptor coupled to adenylate cyclase activation, whereas UTP only acts at the P2Y2 receptor (10, 23). The fact that it is activated to the same extent by ATP and UTP suggests that PKC-µ is only involved in the P2Y2 signaling pathway. That notion is confirmed by the finding that other agents that activate adenylate cyclase-coupled receptors do not activate PKC-µ.
There are few previous studies on the identification of PKC isoforms
activated by P2Y2 agonists.
PKC-, -
, and -
were reported to be activated by
P2Y2 receptors in rat renal
mesangial cells (19). That is clearly different from the situation in
type II cells where PKC-
is not present (11, 16) and PKC-
and
PKC-
are not activated by ATP or UTP. Furthermore, PKC-µ was not
detected in the mesangial cells (19). Patel et al. (18) also suggested that PKC-
, but not PKC-
, is activated by both
P2Y1 and
P2Y2 agonists in bovine aortic
endothelial cells. However, their conclusion was based on PKC inhibitor
data rather than on direct isomer activation, and they left open the
possibility of activation of an unidentified PKC isomer. In addition,
Patel et al. did not examine PKC-µ and did not distinguish between
activation by P2Y1 and
P2Y2 receptors.
In summary, we have found that PKC-µ is activated by P2Y2 agonists as well as by TPA and dioctanoylglycerol in type II cells. ATP and UTP activate PKC-µ to the same extent, but the effects of TPA and dioctanoylglycerol are more pronounced. In addition, TPA and dioctanoylglycerol activate additional PKC isomers that are not activated by the P2Y2 agonists. Because it is activated by different types of secretagogues, PKC-µ may have an important role in the physiological regulation of surfactant secretion.
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ACKNOWLEDGEMENTS |
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This work was supported by National Heart, Lung, and Blood Institute Grant HL-31175.
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FOOTNOTES |
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A preliminary report of these data was presented at the annual meeting of The American Society for Cell Biology in San Francisco, CA, on December 12-16, 1998. An abstract has been published (Mol. Biol. Cell 9: 497a, 1998).
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. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: S. A. Rooney, Dept. of Pediatrics, Yale Univ. School of Medicine, PO Box 208064, New Haven, CT 06520-8064 (E-mail: Seamus.Rooney{at}Yale.edu).
Received 10 December 1998; accepted in final form 22 March 1999.
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