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Department of Biochemistry and Molecular Biology (K.L.D., C.Y.,
B.M.S.) University of Texas Medical School at Houston Houston,
Texas 77030
Department of Medicine (D.W.C.) Veterans
Affairs Medical Center and Oregon Health Science University
Portland, Oregon 97201
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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q-stimulated
phosphatidylinositide turnover. The dramatic loss of the
cAMP-inhibitory effect on day 21 of pregnancy may alter the balance
between uterine contraction and relaxation near parturition. The
changes in the relative concentrations of PKA and PP2B associated with
AKAP150 are consistent with a functional role for AKAP150 scaffolding
in the alteration of cellular signaling. |
INTRODUCTION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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In the uterus, elevation of cAMP concentration has been correlated with
relaxation of the myometrium, and the cAMP pathway has been targeted by
some tocolytics to control preterm labor (5). We have recently shown
that the cAMP- dependent protein kinase (PKA) inhibits the
Gq-stimulated activation of PLCß3 (6) and
is localized at the plasma membrane through association with a 86-kDa
AKAP in human myometrial cells (6A ).
During pregnancy, the ability of ß-adrenergic agonists to inhibit
contraction and to generate cAMP decreases with gestational age in both
human and rat myometrium (7, 8). It has been suggested that this
decrease is the result of changes in the signaling pathways involved in
cAMP generation. ß-Adrenergic receptors, Gs and
adenylyl cyclase expression, and Gs-stimulated adenylyl
cyclase activity decrease in term rat and human myometrium (8, 9, 10, 11, 12).
However, in the day 21 pregnant rat myometrium, forskolin did not
inhibit oxytocin-induced phosphatidylinositide turnover, although it
did increase cAMP concentration (13). These data suggested that the
cAMP-mediated inhibitory mechanism itself may also decline at the end
of pregnancy.
In the present study, we report a dramatic decline in the ability of chlorophenylthio (CPT)-cAMP to inhibit oxytocin-stimulated phosphatidylinositide turnover on day 21 of pregnancy near term. This decline in the cAMP-inhibitory mechanism was accompanied by a reciprocal change in the concentrations of PKA and protein phosphatase 2B (PP2B) associated with a plasma membrane AKAP of 150 kDa. These changes indicate that AKAP150 can act as a scaffolding protein and that the gestation-associated shift in the enzymes associated with AKAP150 may help determine the physiological state of the uterus.
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RESULTS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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). A TGOT
concentration of 200 nM, close to the EC50, was
used in all subsequent experiments.
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). The
cAMP-inhibitory effect was also demonstrated on days 12, 15, and 20, as
summarized in Fig. 2C. However, on day 21, the results were strikingly
different (Fig. 2B). Neither CPT-cAMP nor isoproterenol inhibited
TGOT-stimulated phosphatidylinositide turnover. The loss of the
cAMP-inhibitory mechanism occurred sharply between days 20 and 21 of
gestation (Fig. 2C). These rats normally deliver on the afternoon of
day 21.
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Another explanation might be that the target protein for PKA has
decreased in concentration in the plasma membrane. We have found that
PKA inhibited the coupling of Gq to PLCß3
as a result of phosphorylation of PLCß3 on
Ser1105 (6). Therefore, a significant decrease in
PLCß3 in the plasma membrane could influence the effect
of cAMP on oxytocin receptor/Gq/PLCß coupling. Figure 3A shows that PLCß1 and
PLCß3 concentrations did not change significantly between
days 19 and 21, as detected by Western blot, whereas Gq
concentration increased. PLCß2 was not detected by
Western blot for either day (data not shown). These data suggest that
the loss of the cAMP-inhibitory mechanism is not due to a significant
decrease in the target PLC.
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shows that the expression of both the
PKA catalytic and regulatory type II subunits decreased dramatically
between days 19 and 21 of pregnancy in purified myometrial plasma
membrane preparations. The changes in protein concentration have been
confirmed in tissue from three separate rats in each group. The
cAMP-stimulated kinase activity was also significantly higher in
pregnant rat myometrial plasma membranes on day 19 of gestation
compared with day 21 (Fig. 4A).
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, no decrease in
AKAP150 was detected by overlay analysis.
An increase in phosphatases at the plasma membrane could
dephosphorylate PKA target proteins and oppose PKA action. Figure 3C
shows changes in concentrations of phosphatases known to associate with
the plasma membrane (16). Although protein phosphatase 1 (PP1)
concentration did not change between days 19 and 21 of pregnancy, PP2B
concentration significantly increased in the plasma membrane on day 21
compared with day 19. Calcium-stimulated PP2B activity in plasma
membranes prepared from myometrium on days 19 and 21 of pregnancy did
not increase significantly under the experimental conditions (Fig. 4B).
Changes in the concentrations of these proteins in total tissue
homogenates are shown in Fig. 5. In
contrast to the decline in PKA concentration in the plasma membrane
between days 19 and 21, total homogenate PKA concentrations increased
over this time interval (Fig. 5B), as did cAMP-stimulated PKA activity
(Fig. 4C). PP2B concentration increased in total tissue homogenates
between days 19 and 21 of pregnancy (Fig. 5C), similar to the increase
in PP2B concentration seen in the plasma membrane (Fig. 5C). The
activity of PP2B in the total homogenates increased between days 19 and
21 as well (Fig. 4D). In contrast, PP1 expression was unchanged in
total homogenates (Fig. 5C).
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summarizes the average changes
in protein expression on day 21 relative to day 19 of gestation in rat
myometrial plasma membranes (A) and total myometrial homogenates (B),
observed in tissue from three separate rats in each group. The most
striking contrast is between the decrease in plasma membrane PKA in the
face of an increase in total PKA and no change in the concentration of
AKAP150. On the other hand, the concentration of PP2B associated with
the plasma membrane paralleled the increase in total cellular
enzyme.
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). The disruption of
PKA/AKAP interaction by S-Ht31 in day 19 cells mimics the lack of
repression by PKA seen in day 21 pregnant rat myometrium, where the
concentration of PKA in the plasma membrane is decreased.
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shows that the amount
of PKA coimmunoprecipitated with AKAP150 dramatically decreased on day
21 of pregnancy compared with day 19. These data correlate with the
decrease in PKA concentration at the plasma membrane that occurred at
this time.
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was stripped and probed with an
antibody against PP2B. Figure 8B shows that PP2B coimmunoprecipitated
with AKAP150. In contrast to PKA, the binding of PP2B to AKAP150
increased on day 21 of pregnancy, in parallel with the increase in PP2B
protein in the membrane. These data suggest that PP2B/AKAP150
association plays a role in the localization of PP2B to the plasma
membrane in the rat myometrium.
Previous data from our laboratory showed that the cAMP-inhibitory
effect on Gq-stimulated PLCß3 activity was
mediated via PKA phosphorylation of PLCß3 (6). Figure 9 shows that day 21 pregnant rat
myometrial extracts dephosphorylated recombinant
32P-labeled PLCß3 by 82% in 15 min at 30
C. In the presence of the specific PP2B autoinhibitory peptide,
32P-PLCß3 was only dephosphorylated 36%,
while it was dephosphorylated 74% in the presence of okadaic acid, a
PP1 and PP2A inhibitor. These data indicate that
32P-PLCß3 is a substrate for PP2B and that
PP2B is the major phosphatase in the myometrial extract
dephosphorylating this protein.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Both Gs concentration and the ability of
Gs to stimulate adenylyl cyclase activity decrease in
the laboring human uterus (10). Furthermore, there is a decrease in
adenylyl cyclase concentration in the day 21 pregnant rat uterus (11).
Therefore, decreased ability of uterine relaxants to generate cAMP
would affect their ability to inhibit phosphatidylinositide turnover.
However, this explanation does not explain the loss of effect of
CPT-cAMP itself on phosphatidylinositide turnover, since this treatment
bypasses the need for the generation of cAMP.
We had found previously that CPT-cAMP inhibited the oxytocin-stimulated increase in phosphatidylinositide turnover in the nonpregnant estrogen-primed rat myometrium (18, 19). In contrast to this finding, Khac et al. (13) found that forskolin did not attenuate the oxytocin-stimulated increase in phosphatidylinositide turnover in the day 21 pregnant rat uterus although it increased cAMP. These apparent discrepancies could be reconciled if the cAMP- inhibitory mechanism decreased near the end of pregnancy. This indeed appears to be the case. Although CPT-cAMP and isoproterenol inhibited the oxytocin-stimulated increase in phosphatidylinositide turnover on days 12–20 of pregnancy in the rat, neither agent inhibited the oxytocin-stimulated increase on day 21.
In the rat myometrium, the predominant PLCß subtypes are
PLCß1 and PLCß3 (20). Phosphorylation of
PLCß3 by PKA inhibits stimulation of this enzyme by
Gq (6). A decrease in the concentration of
PLCß3 would decrease the sensitivity of
phosphatidylinositide turnover to cAMP. Indeed, PLCß3
mRNA has been reported to decrease in the 21 day pregnant rat
myometrium (21). However, no significant changes were seen in
PLCß3 protein concentration at the level of the
myometrial plasma membrane or in total cellular protein between days 19
and 21 of gestation. The concentration of Gq increased,
consistent with previous reports (22). These data suggest that the lack
of cAMP inhibition of phosphatidylinositide turnover on day 21 is not
the result of a decrease in PLCß3 concentration. It is
unlikely that a shift in the relative coupling of the oxytocin receptor
from Gq to Gi (23) could contribute to
the loss of the effect of cAMP, since Gß
-stimulated
PLCß3 is also inhibited by PKA (24).
A decrease in PKA activity could also contribute to a decrease in the cAMP-inhibitory response. Consistent with this hypothesis, PKA concentration and activity decreased in myometrial plasma membranes on day 21 of gestation compared with day 19. This change in PKA concentration was not the result of a decrease in cellular PKA concentration, but rather a decrease in the localization of PKA to the plasma membrane. The amount of PKA coimmunoprecipitated with plasma membrane-associated AKAP150 was greater on day 19 of gestation than on day 21. Disruption of PKA/AKAP association reversed the cAMP-mediated inhibitory effect in the day 19 pregnant rat myometrium, mimicking the lack of cAMP responsiveness seen on day 21. These data suggest that PKA localized to the plasma membrane through the association with AKAP150 is necessary for the cAMP-inhibitory mechanism and indicate that pregnancy-related mechanisms regulate the localization of PKA in the myometrium.
Dephosphorylation of proteins is of equal importance as phosphorylation
in the regulation of protein activity. Western blot analysis of
myometrial plasma membrane demonstrated a significant increase in PP2B
expression on day 21 of pregnancy compared with day 19 in both plasma
membrane fractions and total homogenates. PP2B was also shown to
associate with AKAP150, suggesting PP2B localization to the plasma
membrane is accomplished via this association. This demonstration that
AKAP150 can associate with proteins other than PKA extends its homology
to AKAP79. In contrast to PKA, more PP2B was associated with AKAP150 on
day 21 than on day 19 of pregnancy. In vitro experiments
demonstrated 32P-labeled PLCß3 could be
dephosphorylated by PP2B, suggesting that PLCß3 could be
a target of PP2B action in vivo. By decreasing the
effectiveness of PKA on the regulation of PLCß3 activity,
PP2B could enhance Gq/PLCß3 coupling,
favoring contraction of the myometrium. The association of PP2B with
AKAP150 could contribute to the lack of a significant change in PP2B
activity associated with the plasma membrane fractions between day 19
and day 21. Interaction of PP2B with AKAP79 inhibits enzyme activity
in vitro (3). However, it has been hypothesized that PP2B
could be activated when locally released from AKAPs under specific
physiological conditions, and therefore the increased concentration
could have functional significance (3).
The association of PKA and PP2B with AKAP150 showed a reciprocal binding pattern, which, in the case of PKA, was not a reflection of changes in tissue PKA expression. Calmodulin binding to AKAP79 decreases PKC binding (4). By analogy, it is possible that the binding affinity of PKA for AKAP150 may decrease as a consequence of PP2B binding, and this possibility is being explored. Understanding the regulation of the association of PKA and PP2B with AKAP150 could be helpful in understanding the control of preterm labor and parturition.
The association of PKA and PP2B with AKAP150 suggests that AKAP150 acts as a scaffolding protein in the myometrium. The gestation-dependent association of these enzymes with AKAP150 in the plasma membrane may help to regulate events controlling the physiological state of the uterus. The higher concentration of PKA associated with AKAP150 on day 19 of pregnancy could favor inhibition of the action of PLCß3, promoting uterine quiescence. On day 21 of pregnancy, the decreased association of PKA and the increased association of PP2B with AKAP150 could diminish PKA action at the plasma membrane, facilitating uterine contraction. These data suggest that AKAPs, functioning as scaffolding proteins, play an important physiological role in events associated with parturition.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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500 U/mg) were
obtained from Sigma (St. Louis, MO). Antibodies against
PLCß1, PLCß2, PLCß3, PP1, PKA
regulatory subunit II (will detect all RII subunits per supplier),
PKA catalytic subunit (cross-reactive with ß and subunits),
Gq/ll, normal mouse IgG, and Protein A- and A/G-agarose
conjugates were obtained from Santa Cruz Biotechnology, Inc. (Santa Cruz, CA). The antiprotein phosphatase 2B (PP2B)
antibody was obtained from Transduction Laboratories (Lexington, KY).
The PKA RII subunit and PP2B autoinhibitory peptides were obtained from
BIOMOL Research Laboratories, Inc. (Plymouth Meeting, PA).
Recombinant purified PLCß3 was prepared as described
previously (6). Goat antirabbit IgG horseradish peroxidase conjugate
was obtained from Bio-Rad Laboratories, Inc. (Hercules,
CA). Cell culture reagents were obtained from Life Technologies, Inc. (Gaithersburg, MD). The AKAP interaction inhibitor peptide
S-Ht31 and the control peptide P-S-Ht31 have been characterized
previously (25). Timed pregnant Sprague Dawley rats were obtained from
Harlan Sprague Dawley, Inc. (Houston, TX) and normally
delivered on the afternoon of day 21 of pregnancy. Thr4,
Gly7-Oxytocin (TGOT) was obtained from Peninsula Laboratories, Inc. (Belmont, CA). -P32-ATP (3000
Ci/mol) and [3H]myoinositol (22.3 Ci/mmol) were obtained
from Dupont-NEN (Boston, MA).
Phosphatidylinositide Turnover
Rats on various days of pregnancy were killed between 0600 and
0800 h by ether excess according to institutional guidelines.
Uteri were cut open, the fetuses and placentae removed, and the
endometrium removed by gentle scraping. The myometrium was cut into
approximately 50-mg strips and labeled with 0.4 µM
myo-[3H]-inositol (8.3 µCi/ml) in 1 ml Kreb-Ringers
(118 mM NaCl, 4.7 mM KCl, 25 mM
NaHCO3, 1.2 mM KH2PO4,
1.2 mM MgSO4, 10 mM glucose, 10
µM myoinositol, 1.2 mM CaCl2, pH
7.4) buffer at 37 C for 3 h in the presence of 5%
CO2/95% O2. The tissue was incubated with 10
mM LiCl in Kreb-Ringers buffer for 10 min. Isoproterenol
and CPT-cAMP were added 15 min before stimulation with various amounts
of TGOT for 3 min. Reactions were terminated by freezing strips in
liquid N2. [3H]Inositol phosphates were
isolated and counted essentially as described previously (19). Data are
expressed as mean ± SE and were analyzed by one-way
ANOVA and Duncan’s modified multiple range test.
Isolation and Culture of Pregnant Rat Myometrial Cells
Isolation of myometrial cells from a day 19 pregnant rat was
performed by the method of Arnaudeau et al. (26) with a few
modifications. The myometrium, isolated as described above, was placed
in HBSS plus 4000 mg/liter glucose, 200 mg/liter CaCl2 and
98 mg/liter MgCl2, minced finely, and shaken at 37 C for 5
min in HBSS containing 0.1% BSA. The tissue was then digested with
0.15% collagenase in HBSS with shaking for 40 min at 37 C. After
centrifugation at 1200 x g for 5 min, the supernatant
was removed and the pellet digested with fresh collagenase for an
additional 40 min. The supernatants were pooled, and the cells washed
with HBSS. The cells were plated in two 150-mm plates, replated 24
h later at 1.8 x 105 in 35-mm plates, and used for
phosphatidylinositide turnover 24 h later.
Immunoblot Analysis
Purified myometrial plasma membranes were prepared as previously
described (27). Protein from either total pregnant myometrium
homogenates (10 µg) or purified myometrial plasma membrane (5 µg)
was subjected to SDS-PAGE in 10% gels and transferred to
nitrocellulose membranes (Millipore Corp., Bedford, MA).
Blots were probed with antibodies, and bands were visualized by
enhanced chemiluminescence (DuPont-NEN).
Immunoprecipitation
Plasma membranes (50 µg) from pregnant rat myometrium on days
19 and 21 of pregnancy were incubated on ice in RIPA buffer (1x
phosphate buffer solution, 1% NP40, 0.5% sodium deoxycholate, 0.1%
SDS, and 1% Triton X-100) with 1 µg normal mouse IgG/ml buffer.
After 30 min, Protein A/G-agarose conjugate was added and the mixture
was centrifuged in a microfuge for 5 min at 4 C. AKAP150 antibody (5
µg) was added to the supernatant and incubated at 4 C with shaking in
RIPA buffer for 18 h. The mixture was incubated for 4 h with
Protein A/G-agarose beads (20 µl) and centrifuged at 5000 x
g. The Protein A/G-agarose bead pellet was washed four times
with RIPA buffer, suspended in electrophoresis loading buffer, and
subjected to SDS-PAGE in 10% gels and the proteins transferred to
nitrocellulose membranes. The blots were probed with antibodies against
PKA catalytic subunit and PP2B.
AKAP Overlay Assay
The AKAP overlay assay is a modified Western blot procedure
(28). Purified plasma membrane protein (15 µg) from pregnant rat
myometrium was subjected to SDS-PAGE in 10% gels and transferred to
nitrocellulose membranes. Blots were probed with radiolabeled
recombinant PKA regulatory subunit type II produced as previously
described (24), and bands were visualized by autoradiography.
PKA Activity
PKA activity was assayed by the method of Roskoski (29) with
minor modifications. Either plasma membrane protein (5 µg) or total
myometrial extracts (10 µg) from myometrium on different days of
pregnancy were incubated in 50 µl of reaction buffer [10
mM Mg acetate, 20 mM Tris-Cl (pH 7.4), 0.5
mM 3-isobutyl-1-methylxanthine, 10 mM
dithiothreitol, 5 mM NaF] containing 2 µM
CPT-cAMP, 30 µM Kemptide (PKA substrate), 100
µM ATP, and 5 µM 32P--ATP.
After 5 min at 30 C, 20 µl of the reaction were spotted onto
phosphocellulose strips and washed five times in 75 mM
phosphoric acid and once in 95% ethanol. Filters were air dried and
counted by liquid scintillation.
PP2B Activity
Substrates were labeled in reaction buffer containing 100
µM ATP, 5 µM 32P--ATP, 20
mM 4-morpholinepropanesulfonic acid, pH 7.0, 2
mM magnesium acetate, 15 mM
ß-mercaptoethanol, and either 94 mM PKA RII peptide or
100 mM recombinant PLCß3(His)6
with PKA catalytic subunit at a molar ratio of 20:1. The mixture was
incubated at 30 C for 30 min.
32P-PLCß3(His)6 was bound to
nickel-nitrilotriacetic acid (Ni-NTA) resin and separated from
free 32P--ATP via centrifugation as described previously
(6).
PP2B activity was measured using either 32P-labeled PKA RII peptide or 32P-labeled PLCß3(His)6. Five micromoles of each labeled substrate were added to 30 µl reaction buffer (40 mM Tris, pH 7.5, 0.1 M KCl, 0.5 mM CaCl2, 6 mM magnesium acetate, 2.5 µM calmodulin, 0.5 mM dithiothreitol, 10 µM IP20) containing either 5 µg total plasma membrane protein or 10 µg total myometrial extracts from the different days of pregnancy. The reactions were incubated for 15 min at 30 C. For experiments using the RII peptide, 20 µl of the reaction mixture were spotted onto phosphocellulose strips and washed five times in 75 mM phosphoric acid and once in 95% ethanol. Filters were air-dried and counted by liquid scintillation.
For experiments using PLCß3(His)6, okadaic acid (15 nM) and PP2B autoinhibitory peptide (4.4 nM) were also added to the reaction mixture where specified. After termination of the reaction, PLCß3(His)6 was bound to Ni-NTA resin and washed, and the pellet was extracted with gel loading buffer. Samples were electrophoresed on 10% SDS-PAGE gels and subjected to autoradiography. Quantitation was accomplished by densitometry.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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This work was supported in part by NIH Grants HD-09618 (B.M.S.), HD36408 (D.W.C.), and T32-HD07325 (K.L.D.)
Received for publication March 18, 1999. Revision received July 23, 1999. Accepted for publication August 11, 1999.
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