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Progesterone Prevents the Pregnancy-Related Decline in Protein Kinase A Association with Rat Myometrial Plasma Membrane and A-Kinase Anchoring Protein¹

^a Department of Biochemistry and Molecular Biology, University of Texas Medical School at Houston, Houston, Texas 77030

	ABSTRACT

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The presence of cAMP-dependent protein kinase (PKA) in the plasma membrane compartment and its association with an A-kinase anchoring protein (AKAP150) is implicated in mediating cAMP regulatory events in the rat myometrium. The association of PKA with purified myometrial plasma membrane declined gradually between Day 16 and Day 21 of gestation, with a decrease of 53% ± 11% of the catalytic subunit and of 61% ± 7% of the regulatory subunit at Day 21 compared with Day 19. To determine the role of progesterone in this association, pregnancy was prolonged by administration of progesterone or shortened by administration of the antiprogestin RU486. Progesterone treatment maintained PKA association with plasma membrane at Day 21 at 123% ± 23% (catalytic subunit) and 92% ± 4% (regulatory subunit) of Day 19 levels. In contrast, protein phosphatase 1, protein phosphatase 2B, phospholipase Cß₃, and AKAP150 concentrations in the plasma membrane did not change over this interval or with progesterone treatment. Changes in PKA coimmunoprecipitated with membrane-associated AKAP150 paralleled those in total plasma membrane on Days 19 and 21 and on Day 21 following progesterone treatment. In contrast, plasma membrane PKA catalytic and regulatory subunits decreased by 20 h after RU486 injection on Day 15 of pregnancy to levels resembling those on Day 21. These data indicate that progesterone prevents the decline in PKA associated with myometrial plasma membrane and with AKAP150 in the pregnant rat. The decrease in membrane-bound PKA between Days 19 and 21 and after RU486 treatment precedes the onset of parturition in both experimental paradigms. The loss of plasma membrane PKA may be critical for the decrease in the inhibitory effect of cAMP on oxytocin-induced phosphatidylinositide turnover that occurs near the end of pregnancy and may contribute to enhanced myometrial contractile responsiveness near term.

cyclic adenosine monophosphate, kinases, parturition, progesterone, signal transduction

	INTRODUCTION

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Cyclic AMP-dependent protein kinase (PKA) is targeted to specific intracellular compartments through its interaction with A-kinase anchoring proteins (AKAPs) [1–3]. This association is important for PKA-mediated phosphorylation and regulation of many proteins. In addition to possessing a PKA regulatory subunit (RII) amphipathic helix binding motif, AKAPs contain unique targeting domains that localize the particular PKA/AKAP complex to different subcellular domains. Individual AKAPs also possess interaction sites for a variety of other proteins including phosphatases, kinases, and phosphodiesterases. There is increasing evidence that the close interaction of PKA with these regulatory molecules can influence signal transduction pathways [4–6]. Thus, AKAPs may act as scaffolding proteins, integrating multiple signaling pathways to transmit specific regulated signals controlling cellular events [1–3].

Human AKAP79 and its rat homolog, AKAP150, are localized to plasma membrane and can bind PKA, protein kinase C, calcineurin, or protein phosphatase 2B, calmodulin, and phosphatidylinositide-4,5-bisphosphate [2, 7, 8]. Dodge et al. [9] found that the ability of PKA to inhibit agonist-stimulated phospholipase C activity depended on the PKA/AKAP interaction in a number of cell types and found the respective AKAPs in human and rat myometrium plasma membrane.

In the myometrium, a number of contractant hormones activate G_q-linked phospholipase C and increase inositol trisphosphate (IP₃) formation [10–12]. Inositol trisphosphate releases Ca²⁺ from intracellular stores, thus promoting contraction. The PKA inhibits G_q-stimulated IP₃ formation as a consequence of phosphorylation of PLCß₃ on Ser¹¹⁰⁵ [13]. As parturition approaches, the uterus is thought to undergo biochemical changes that shift the balance from relaxant to contractant pathways [12, 14]. Consistent with this concept, the ability of 8-(4-chlorophenylthio)-cAMP (CPT-cAMP) to inhibit oxytocin-stimulated phosphatidylinositide turnover diminishes markedly between Days 19 and 21 of gestation in the pregnant rat myometrium [15]. Accompanying this change is a marked decrease in PKA association with the plasma membrane and with AKAP150. Over this same period, there is a marked increase in the plasma estrogen/progesterone ratio in the rat [16, 17].

The present study was designed to determine if progesterone influences the association of PKA with myometrial plasma membrane. Progesterone was administered to prolong pregnancy and the antiprogesterone RU486 was used to shorten pregnancy and the effect on plasma membrane PKA examined.

	MATERIALS AND METHODS

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Materials

Polyclonal antibodies against PKA catalytic subunit , PKA II regulatory subunit, protein phosphatase 2B catalytic subunit (PP2B), AKAP150, and donkey anti-rabbit IgG horseradish peroxidase conjugate were obtained from Santa Cruz Biotechnology, Inc. (Santa Cruz, CA). Monoclonal antibody against PP2B catalytic subunit A was obtained from Transduction Lab (Lexington, KY). Mifepristone (RU486) was purchased from Biomol (Plymouth Meeting, PA). Cell culture reagents were obtained from Life Technologies, Inc. (Gaithersburg, MD). Other chemicals, protease inhibitors, and protein A beads were purchased from Sigma (St. Louis, MO). Gradient polyacrylamide gels (4%–15%) were purchased from BioRad (Hercules, CA).

Timed pregnant Sprague Dawley rats were obtained from Harlan Sprague Dawley, Inc. (Indianapolis, IN); the day when the vaginal plug was observed was dated Day 0. The experiments were conducted in accordance with institutional practices in an Association for Assessment and Accreditation for Laboratory Animal Care-accredited facility.

Hormone Treatment and Plasma Membrane Preparation

Progesterone (10 mg/day s.c. in oil) was injected from Day 17 of pregnancy, and animals were killed at the day indicated. RU486 (3 mg in oil) was injected on Day 15 of pregnancy, and animals were killed after 6, 12, and 20 h. Myometrial plasma membranes from individual animals were prepared by discontinuous sucrose density centrifugation as described previously [10]. Membranes were resuspended and stored at -80°C in sample buffer (10 mM Tris-HCl; 250 mM sucrose; 1 mM EGTA; 1 µg/ml each leupeptin, pepstatin A, and aprotinin).

Immunoprecipitation

Plasma membrane isolated from individual animals (25–50 µg protein, determined by Lowry protein assay) was incubated at 4°C overnight with anti-AKAP150 antibody (40 µg/ml) and protein A beads in RIPA buffer (10 mM Na₂HPO₄; 1.7 mM KH₂PO₄; 150 mM NaCl; 1% NP40; 0.5% sodium deoxycholate; 0.1% SDS; 1% Triton X-100; 1 mM EDTA; 1 mM PMSF; 1 µg/ml each leupeptin, pepstatin A, and aprotinin). The mixtures were centrifuged at 10 600 x g for 10 min, and the pellets were washed four times with RIPA buffer, suspended in electrophoresis loading buffer (62.5 mM Tris-HCl, pH. 6.8, 4 M urea, 10% glycerol, 2% SDS, 0.001% ß-mercaptoethanol, 0.002% bromophenol blue), boiled, and centrifuged. The supernatants were subjected to SDS-PAGE in 4%–15% gels and immunoblot analysis as described below. No AKAP150 was detected in the plasma membrane extract after immunoprecipitation.

Western Blot Analysis

Myometrial plasma membrane prepared from individual animals (5–10 µg protein) was subjected to SDS-PAGE in 4%–15% gels. Protein was transferred at 100 V for 45 min to nitrocellulose membrane (Schleicher and Schuell, Keene, NH); blots were probed with antibodies (1:500 dilution) and the bands visualized by enhanced chemiluminescence (Amersham Pharmacia Biotech, Piscataway, NJ). Equality of loading was judged by comparison with Coomassie blue staining of equivalent samples. Quantitation was accomplished by scanning both autoradiographs of immunoblots and Coomassie blue-stained gels with a ScanMaker III (Microtek, Redondo Beach, CA) and determining the density with the NIH Image 1.62f program. Samples were normalized to Coomassie blue staining.

Data Analysis

Where appropriate, data are expressed as the mean ± SEM of samples from 3–6 separate animals and were analyzed by one-way analysis of variance and Duncan modified multiple range test.

	RESULTS

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Progesterone Prevents the Decline in Myometrial Plasma Membrane PKA at Late Gestation

To examine whether the change in association of PKA with the myometrial plasma membrane prior to parturition was related to the reduction in progesterone near term, we determined the effect of treatment with progesterone on plasma membrane PKA. Plasma membrane PKA catalytic subunit of pregnant rats gradually decreased between Days 16 and 21, with a decrease of 53% ± 11% (n = 5) at Day 21 compared with Day 19 (Fig. 1A). The PKA regulatory subunit also gradually decreased as well, with a decrease of 61% ± 7% (n = 3) between Days 19 and 21 (Fig. 1B). Based on information provided by the supplier and our observations, these animals normally deliver at approximately Day 21.5. Progesterone treatment prolonged gestation until after Day 23 and prevented the decline in plasma membrane PKA catalytic subunit at Day 21 (123% ± 23% [n = 5] of Day 19 concentrations). Similar results were observed with PKA regulatory subunit (92% ± 4% [n = 3] of Day 19 concentration); PKA in total tissue homogenates was unchanged between Days 19 and 21 (data not shown).

View larger version (26K): [in this window] [in a new window]   FIG. 1. Western blot analysis of myometrial plasma membrane protein from pregnant rats on Days 16–21 and pregnant rats treated with progesterone (P) and RU486 (RU). Sample blots from one set of animals probed with antibodies against PKA catalytic subunit (PKA-cat) (A) and PKA regulatory subunit (PKA-reg) (B) are shown. The bars represent data from 3–6 animals, expressed as mean ± SEM of PKA concentration normalized to Day 19 control. Data were analyzed as described in Materials and Methods. Significant differences between groups at P < 0.05 are designated by different lowercase letters

In contrast with the decline in plasma membrane PKA, the concentrations of other membrane proteins potentially involved in signaling, including AKAP150, phospholipase Cß₃, protein phosphatase 1, and protein phosphatase 2B did not change significantly between Days 19 and 21 of pregnancy (Fig. 2). The concentrations of these proteins in plasma membrane were also not affected by progesterone treatment (Fig. 2).

View larger version (41K): [in this window] [in a new window]   FIG. 2. Concentrations of protein phosphatase 2B (PP2B), protein phosphatase 1 (PP1), phospholipase Cß3 (PLCß3), and AKAP 150 (AKAP) as determined by immunoblot in myometrial plasma membranes from Day 19 and Day 21 pregnant rats and from Day 21 pregnant rats treated from Day 17 with progesterone (P). Data are expressed as mean ± SEM (n = 3–5) for the respective proteins, normalized to Day 19 control, and were analyzed as described in Figure 1

In addition to measuring total plasma membrane PKA and AKAP, we also examined AKAP150 immunoprecipitates in membrane extracts for the presence of PKA. The amount of PKA catalytic subunit coprecipitating with AKAP150 declined between Days 19 and 21 by 44% ± 4% (Fig. 3A). In contrast, progesterone treatment prevented this decline (98% ± 4% of Day 19 control). The relative changes in immunoprecipitated PKA catalytic subunit paralleled those in the total plasma membrane from these same animals (Fig. 3A). Figure 3C shows that AKAP150 and PKA catalytic subunit can be coimmunoprecipitated also with anti-RII antibody.

View larger version (30K): [in this window] [in a new window]   FIG. 3. A) Concentrations of PKA catalytic subunit coimmunoprecipitated with AKAP150 from plasma membrane (50 µg protein) extracts and in total plasma membrane (10 µg protein) from Days 19 and 21 and in progesterone (P)-treated Day 21 pregnant rat myometrium. Representative blots and bar graphs showing mean ± SEM (n = 3) of data normalized to Day 19 control are shown. Significant differences between groups at P < 0.05 are designated by different lowercase letters. B) Concentrations of PKA catalytic subunit coimmunoprecipitated with AKAP150 from plasma membrane (50 µg protein) extracts and in total plasma membrane (10 µg protein) from Day 16 pregnant rat myometrium and myometrium isolated 20 h after treatment with RU486 (RU) on Day 15. Data are presented as in A. C) The presence of both of AKAP150 and PKA-cat in Day 21 progesterone-treated myometrial plasma membrane extract (400 µg protein) immunoprecipitated with anti-RII antibody (4 µg)

In order to determine whether progesterone, estrogen, or both had a direct effect on plasma membrane PKA, adult ovariectomized rats were treated with 10 mg/day progesterone (P), 50 µg/day estradiol (E), or progesterone plus estradiol in different combinations. None of the hormone treatments affected plasma membrane PKA catalytic subunit content (mean, n = 2): 1) ovariectomy 1 day followed by P or E treatment for 2 days (P:1.0 and E:1.3-fold over control); 2) ovariectomy 4 days followed by P, E, or P+E for 2 days (P:1.1, E:1.1, and P+E:1.1-fold over control); 3) ovariectomy 7 days followed by P, E, or P+E for 3 days (P:0.7, E:0.8, and P+E:0.8-fold over control). The PKA catalytic subunit concentration in 4-day ovariectomized rat plasma membrane was similar to that of Day 19 of pregnancy, as determined in the same immunoblot.

RU486 Treatment Decreases PKA Association with Myometrial Plasma Membrane

RU486 is an antiprogestin that acts at the level of the progesterone receptor and triggers premature labor and delivery in rats [18]. To determine the effect of interfering with the action of progesterone on myometrial plasma membrane PKA, Day 15 pregnant rats were treated with RU486. In these experiments, the rats showed signs of labor after 20 h and started delivering 24–27 h after treatment. At 20 h after treatment, plasma membrane PKA catalytic subunit had declined 44% ± 14% relative to the Day 19 level, in the same range as the change seen on Day 21 (Fig. 1A). Similar changes were seen in PKA regulatory subunit (Fig. 1B). PKA catalytic subunit coimmunoprecipitating with AKAP150 decreased 20 h after RU486 treatment by approximately the same proportion as plasma membrane PKA (Fig. 3B). There was no change in plasma membrane AKAP150 with or without RU486 treatment for 20 h (data not shown).

The time course of the response to RU486 is shown in Figure 4. In control pregnant animals, plasma membrane PKA catalytic subunit did not change over the 20 h following oil injection. PKA association with the plasma membrane after RU486 treatment was unchanged at 6 h but declined gradually over 12 and 20 h. Catalytic subunit declined by 25% and 46% of the control level with 12 and 20 h, respectively (Fig. 4A), and regulatory subunit declined by 28% and 37% over the same time period (Fig. 4B).

View larger version (11K): [in this window] [in a new window]   FIG. 4. Time course of the effect of RU486 treatment on Day 15 of pregnancy on the amount of PKA catalytic subunit (A) and PKA regulatory subunit (B) in the myometrial plasma membrane. Individual data points for two rats/group, normalized to protein and expressed relative to the 6-h control, are presented

	DISCUSSION

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We previously found that PKA association with pregnant myometrial plasma membrane decreased near term (Day 21), coincident with the loss of the inhibitory effect of cAMP on oxytocin-stimulated phosphatidylinositide turnover [15]. The data presented here demonstrate that progesterone could prevent the decline in plasma membrane and AKAP-associated PKA that occurs at Day 21 of pregnancy. Moreover, the antiprogestin RU486 provoked a gradual decline of PKA in plasma membrane on Day 21 pregnant animals. Both in the approach to normal delivery and after RU486 treatment, this change in PKA occurred without a change in the plasma membrane AKAP150 concentration. These data are consistent with a positive effect of progesterone on the association of PKA with myometrial plasma membrane and with membrane-associated AKAP150 in the pregnant rat.

The changes in plasma membrane PKA over pregnancy and after progesterone treatment were specific for this protein. In addition to AKAP150, the concentrations of protein phosphatase 1, protein phosphatase 2B, and phospholipase Cß₃ were unchanged under these conditions. These data are consistent with and extend our previous observations [15] except that we had noted a concomitant increase in protein phosphatase 2B at Day 21. Although increases were sometimes seen in the present study, they were not consistent and may occur over a specific time period that is difficult to reproduce. In any case, the ratio of myometrial plasma membrane PKA to protein phosphatase 2B decreases at the end of normal pregnancy.

Little is known about the mechanisms that regulate AKAP distribution and PKA/AKAP affinity. AKAP79 can be phosphorylated by PKA and protein kinase C and regulated by calcium-calmodulin [7]. In HEK293 cells, overexpressed AKAP79 moved from membrane to cytosol upon activation of protein kinase C but not PKA [7], whereas movement of endogenous AKAP150 in rat pancreatic cells to the soluble fraction was markedly increased by forskolin treatment [6]. Phosphorylation of the RII subunit has been reported to increase its binding to AKAP100 and AKAP15/18 [19]. These data suggest that covalent modification of RII or an AKAP could potentially alter affinity and cellular location of these proteins in a cell-specific manner. In the pregnant rat myometrium, PKA but not AKAP150 decreased in plasma membrane as term approached. This is unlikely to be directly mediated by phosphorylation in response to progesterone. The time course of the effect of RU486 (over 20 h) is more consistent with an effect on gene regulation. The fact that progesterone did not increase plasma membrane PKA in the ovariectomized rat model suggests that the effects may be indirect and dependent on specific conditions that pertain in pregnancy. Plasma membrane PKA declines prior to delivery at a time when the estradiol/progesterone ratio has markedly increased [16, 17]. Therefore, if estradiol were to have an effect, it would be predicted to decrease membrane-associated PKA. Although the studies described here do not directly rule out a negative influence of estrogen, it is unlikely that progesterone is overcoming and RU486 unmasking such an effect since estradiol did not decrease plasma PKA in the ovariectomized rat model.

The decrease in membrane-bound PKA between Days 19 and 21 and after RU486 precedes the onset of parturition in both experimental paradigms. The decline in membrane- and AKAP150-associated PKA near term is accompanied by a decrease in the inhibitory effect of cAMP on agonist-induced phosphoinositide turnover [15]. This inhibitory effect was dependent on a PKA/AKAP150 interaction and was attenuated by the PKA/AKAP interaction inhibitor S-Ht31. It remains to be determined whether other effects of cAMP in myometrial membranes are as significantly affected.

Anchoring PKA has a significant effect on cAMP signal transduction, both in the localized environment of the signaling complex and at additional target sites in the cell [2, 3]. Recent studies point to a physiological role for colocalization of PKA and either a protein phosphatase or phosphodiesterase on the same AKAP in the localized control of signaling [4–6]. Since PLCß₃ is a substrate both for PKA and protein phosphatase 2B [13, 15], the colocalization of these two enzymes on AKAP150 may facilitate localized control of phosphatidylinositide turnover mediated by this enzyme.

In summary, we have shown that PKA association with the myometrial plasma membrane and with AKAP150 declines at the end of pregnancy and that this decline is attentuated by progesterone and promoted by an antiprogestin. This is the first report of an effect of steroid hormone treatment on association of PKA with a plasma membrane and with an AKAP. Moreover, the decline in plasma membrane PKA during pregnancy accompanies the loss of the PKA-mediated inhibitory effect of cAMP on oxytocin-stimulated phosphatidylinositide turnover. Therefore, progesterone may promote a localized cAMP inhibitory pathway that attenuates activation of PLCß, generation of IP₃, and release of intracellular Ca²⁺ prior to parturition.

	FOOTNOTES

 
First decision: 19 December 2001.

¹ Supported in part by HD09618 (B.M.S.).

² Correspondence: Chun-Ying Ku, Department of Biochemistry and Molecular Biology, University of Texas Medical School at Houston, P.O. Box 20708, Houston, TX 77225. FAX: 713 500 0652; chun-ying.ku{at}uth.tmc.edu

Accepted: March 18, 2002.

Received: December 5, 2001.

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal My Folders Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ku, C.-Y. Articles by Sanborn, B. M. Search for Related Content PubMed PubMed Citation Articles by Ku, C.-Y. Articles by Sanborn, B. M. Agricola Articles by Ku, C.-Y. Articles by Sanborn, B. M.