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Section on Endocrine Physiology, Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892
Address all correspondence and requests for reprints to: Cristina Rabadan-Diehl, Section on Endocrine Physiology, Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Building 10, Room 10N262, 10 Center Drive MSC 1862, Bethesda, Maryland 20892-1862. E-mail: rabadanc{at}cc1.nichd.nih.gov
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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q, which may account for the potentiating
effect of glucocorticoid on ligand-stimulated IP. The data demonstrate
that glucocorticoids increase coupling of the V1b-R with PLC thereby
providing a mechanism by which VP facilitates corticotroph
responsiveness in spite of elevated levels of plasma glucocorticoids
during stress. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The actions of VP are mediated by membrane receptors belonging to the G protein-coupled membrane receptor superfamily (8). So far, three major receptor subtypes have been identified, kidney V2 receptors, which are linked to the guanyl nucleotide binding protein, Gs, and adenylyl cyclase; V1a receptors, coupled to phospholipase C (PLC), present in liver and vascular smooth muscle, and the pituitary V1b-R, also linked to PLC (8, 9, 10). It is known that the GTP-binding protein, Gq, is responsible for coupling V1a receptors (11, 12), and presumably V1b receptors, to PLC.
Evidence indicates that VP plays a primary role in the regulation of the HPA axis during adaptation to stress (5). In a number of chronic stress paradigms, the expression of VP in parvicellular neurons of the PVN, and VP secretion into the pituitary portal circulation, increases (5, 6, 13, 14). Stress also up-regulates the number of VP receptors in the anterior pituitary, increasing the ACTH-releasing activity of the peptide (15). In addition, in vitro studies have shown that activation of ACTH secretion by VP is less sensitive to feedback inhibition by glucocorticoids than that to CRH (16, 17). Because glucocorticoid administration results in pituitary VP receptor loss (18, 19), it is possible that VP receptor activity is regulated at the postreceptor level.
The purpose of these studies was to further investigate the effect of glucocorticoids on V1b-R regulation, and to determine whether glucocorticoids can influence V1b-R signaling. VP binding, V1b-R messenger RNA (mRNA), and VP-stimulated IP formation were measured after long-term glucocorticoid administration in vivo and in vitro. The results demonstrate that prolonged exposure to glucocorticoids decreases the number of pituitary VP receptors while increasing their coupling efficiency. This potentiation was shown to be independent of hypothalamic factors and to be due in part to an increase in the guanyl nucleotide binding protein, Gq.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Anterior pituitary cultures
Anterior pituitaries were collected in medium 199, cells
dispersed by trypsin digestion as previously described (20), and plated
into 24-well plates at a density of 500,000 cells/well for IP
determination or in 75-mm2 flasks at 10 million cells/flask
for Western blot. Cells were cultured in medium 199 with Earle’s salts
supplemented with 10% horse serum for 48 h and then changed to
medium 199 containing 0.1% BSA with or without glucocorticoids for 7
days. Medium was changed every 2 days.
Quantitation of V1b-R mRNA
V1b-R mRNA was measured by Northern blot analysis as previously
described (21), using a 32P-labeled random primed 363-bp
complementary DNA probe, extending from outside of the third
trans-membrane domain into the third cytoplasmic loop of the
rat V1b-R. Radioactivity hybridized to the 3.7- and 3.2-kb bands
corresponding to the V1b-R mRNA was measured using a Fuji bioimaging
analyzer and expressed in arbitrary units, which are directly
proportional to the radiation dose. Values of the V1b-R bands were
normalized per 100 Fuji units of cyclophilin, measured in the same
hybridization (21).
Inositol phosphates determination
In the experiments where dexamethasone was administered in
vivo, quartered hemipituitaries were incubated with 30 µCi of
myo-[3H]inositol (100 Ci/mmol, Amersham,
Arlington Heights, IL) in 250 µl of medium 199 without inositol for
3 h, at 37 C, under 95% O2/5% CO2. After
washing in medium 199 containing 0.1% BSA and 10 mM LiCl,
followed by 10-min preincubation, paired hemipituitary quarters were
incubated with and without 100 nM arginine-VP (Sigma, St.
Louis, MO) for 15 min. Incubations were terminated by addition of 250
µl of stop solution (1 M KOH, 18 mM sodium
tetraborate, 3.8 mM EDTA, 7.6 mM NaOH),
neutralized with 7.5% HCl. Total IP were extracted and separated by
anion exchange chromatography using Dowex columns as previously
described (15, 22) (Bio-Rad, Hercules, CA).
For in vitro experiments, anterior pituitary cells cultured in 24-well plates were labeled with 2.5 µCi/ml of myo-[3H]inositol/well for 48 h, washed with media containing 0.1% BSA and 10 mM LiCl, and then incubated for 15 min under the conditions indicated in results and figure legends. Incubations were stopped by addition of one volume of cold stop solution followed by neutralization with 7.5% HCl. After anion exchange chromatography, total IP were measured in a liquid scintillation counter.
Measurement of VP receptors
VP receptors were measured by binding of [H3]-VP
to 30,000 x g membrane fractions prepared from pools
of five pituitaries as previously described (15). Binding affinity and
receptor concentration were calculated by Scatchard analysis using the
computer program Ligand (23) (NIMH, NIH).
Quantitation of Gq immunoreactivity
Single pituitaries from control and dexamethasone-treated rats,
or cultured anterior pituitary cells treated with dexamethasone, were
homogenized in 3 ml of 20 mM NaHC03 containing
5 mM EDTA and centrifuged for 30 min at 48,000 x
g at 4 C. Pellets were lysed in 50 mM Tris-HCl,
pH 7.4, containing 5 mM MgCl2, 2 mM
EGTA, 1% Triton X-100, 0.1 mM PMSF, 100 KIU/ml aprotinin,
and 1 mM DTT for 90 min at 4 C in a shaking bath. After
centrifugation at 14,000 rpm for 30 min, protein content was determined
using Bio-Rad protein assay reagent (Richmond, CA), and 50 µg of
protein were separated by electrophoresis on a 12% polyacrylamide gel.
The content of Gq was determined by Western blot analysis
using a polyclonal antibody directed to the carboxyl terminus of
Gq/11 (24) at a 1:350 dilution, and an
enhanced chemiluminescence detection system (Amersham). To confirm the
data obtained with the later antibody, additional experiments were
performed using an affinity purified antibody, specific
anti-Gq raised against amino acids 115 to 133 of the
protein (Calbiochem, San Diego, CA). After exposure to film, light
transmittance of the 42-kDa band corresponding to Gq was
quantitated using a computerized image analysis system (Imaging
Research, St Catherine, Ontario, Canada).
Statistical analysis
Data are presented as the mean and SE of the values
in the number of experiments indicated in Results or in the
figure legends, or expressed as percent change from basal or
nondexamethasone-treated controls. Experiments in primary pituitary
cell cultures were performed in duplicate or triplicate incubations,
each in a different cell preparation. Statistical significance of the
differences between experimental groups was determined by ANOVA
followed by the Fisher test for multiple group comparisons.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, top).
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, middle).
To investigate whether the decrease in VP binding was associated with
changes in biological response to VP, the ability of VP to stimulate IP
formation was studied in quartered hemipituitaries of rats that had
received chronic dexamethasone injections. In spite of the decrease in
VP binding in dexamethasone-treated rats, VP-stimulated IP formation
was 33% higher than in control rats (n = 11, P <
0.001) (Fig. 1, bottom).
Effects of glucocorticoids in vitro
To determine whether glucocorticoids regulate the coupling of the
V1b receptor directly in the pituitary, or indirectly through
inhibition of hypothalamic CRH and VP, the effect of glucocorticoids on
inositol phosphate formation was studied in anterior pituitary cells
in vitro. Preincubation of cultured anterior pituitary cells
for 7 days with dexamethasone or the natural glucocorticoid,
corticosterone, had no significant effect on basal IP formation, but
potentiated VP-stimulated IP formation (Table 1). This effect was maximal with the
lowest concentration of steroid used. The potentiation of VP-stimulated
inositol phosphate formation was mediated by glucocorticoid receptors,
as shown by the ability of the glucocorticoid antagonist, RU 40555, but
not the mineralocorticoid antagonist, spironolactone, to prevent
the effect of corticosterone (Table 1).
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. Basal IP formation was not affected by
dexamethasone preincubation at any time point. Twenty-four or 48 h
preincubation with dexamethasone caused a small but significant
potentiation of VP-stimulated IP formation (35 ± 9.2%,
P < 0.01, and 41 ± 18%, P <
0.05), over the values in VP-stimulated control cells, respectively).
Higher potentiation of 82 ± 31.3%, P < 0.01),
and 89 ± 19.3%, P < 0.01, over the
VP-stimulated values in control cells was observed in cells
preincubated with dexamethasone for 4 or 7 days, respectively.
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. Seven days preincubation of cultured
anterior pituitary cells with 10 nM dexamethasone
potentiated the stimulatory effect of VP on IP formation over the
entire dose response. In two experiments, dexamethasone preincubation
enhanced IP stimulation by the lower concentration of VP by 28%,
(P < 0.05). A more marked potentiation of about 100%
was observed with maximal stimulatory concentrations of VP.
Dexamethasone preincubation did not change the half maximal
concentration (ED50) of VP for stimulation of IP formation
(ED50 1.6 ± 0.3 and 1.5 ± 0.2 nM,
with and without dexamethasone, respectively).
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). Because VP is known to interact with
the oxytocin receptor (25), and oxytocin receptors are present in
lactotrophs (26) and gonadotrophs (27), it was important to determine
whether the effect of VP reflects V1b-R in the corticotroph or
interactions with oxytocin receptors. The oxytocin antagonist,
L-368,899 (Merck Research Laboratories, West Point, PA), completely
prevented the stimulatory effect of oxytocin on IP formation in Chinese
hamster ovary cells transfected with the oxytocin receptor but not the
stimulation by VP in AtT-20 cells transfected with the V1b receptor
(not shown). In primary pituitary cells, oxytocin had only a minor
stimulatory effect on IP formation to values not statistically
significantly different from basal. IP formation increased about 5-fold
after incubation with 100 nM VP, and this effect was not
significantly reduced by the oxytocin antagonist. The potentiating
effect of dexamethasone on VP-stimulated IP formation was unaffected by
the oxytocin antagonist (Table 3).
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, increasing calcium from 0 to 1.5
mM or adding 0.1 mM EGTA during incubation with
VP, had no effect on basal VP-stimulated IP formation, or on the
ability of dexamethasone preincubation to potentiate the stimulatory
effect.
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, VP-stimulated IP formation was potentiated by 28%, P
< 0.01, and 82%, P < 0.01, in cells preincubated
with 10 nM dexamethasone for 24 h or 7 days,
respectively. In contrast to VP, the stimulatory effect of ionomycin
was reduced by 20%, P < 0.05, after 24 h
preincubation with dexamethasone, and was similar to control cells
after 7 days dexamethasone pretreatment (Fig. 5).
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, daily injection of dexamethasone
for 7 days in rats caused a 2-fold increase in irGq in
anterior pituitary membranes (P < 0.05). Incubation of
cultured pituitary cells with dexamethasone resulted in similar
increases in irGq as measured by Western blot using either
the antibody recognizing Gq/11 or the
Gq-specific antibody (Fig. 7a). The pooled values from the
experiments with both antibodies, immunoreactive Gq
increased by 78%, P < 0.05 (n = 4), and 119%,
P < 0.01 (n = 5), over the values in
nondexamethasone-treated cells, after 24 h or 7 days preincubation
with dexamethasone, respectively (Fig. 7b).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Not readily predictable was the fact the decrease in VP binding after glucocorticoid administration was not associated with decreases in V1b receptor mRNA. This lack of correlation between V1b-R mRNA and VP receptor number indicates that steady-state mRNA levels are not a primary determinant of receptor number. It is noteworthy that glucocorticoid withdrawal during long-term adrenalectomy also results in VP binding down-regulation but normal levels of V1b receptor mRNA (28). This paradoxical effect probably reflects interactions between glucocorticoids and hypothalamic factors in regulating V1b receptor number. Because glucocorticoids inhibit the expression and secretion of CRH and VP from parvicellular neurons (29, 30, 31), exogenous glucocorticoid excess may directly inhibit V1b-R synthesis at the posttranscriptional level, whereas a hypersecretion of hypothalamic regulators, mainly VP, would mediate the decrease of VP binding during adrenalectomy (18). From this perspective, the stimulatory effect of glucocorticoids on V1b receptor mRNA may be critical to sustain receptor synthesis and the increases in VP binding observed during stress (15).
While the experiments confirm previous reports showing pituitary VP receptor down-regulation after glucocorticoid administration (18, 19), the finding of increased VP-stimulated IP formation in pituitary fragments of dexamethasone-treated rats was unexpected. The paradoxical enhancement of VP-stimulated IP formation in the presence of reduced receptor content suggested that glucocorticoids alter the secretory effect of VP at a postreceptor level, possibly by increasing the coupling efficiency of the receptor to phospholipase C. Removal of endogenous glucocorticoids by surgical adrenalectomy also results in VP receptor down-regulation (4). However, in contrast to the effects of glucocorticoid administration, the loss of VP receptors following adrenalectomy is accompanied by a corresponding blunting of IP responses to VP (32). If glucocorticoids enhance VP-stimulated IP messenger formation as shown by the present data, it is likely that in addition to receptor down-regulation, decreased receptor coupling due to the lack of glucocorticoids contributes to decreased pituitary responses to VP observed during adrenalectomy.
Glucocorticoids administered in vivo could affect the coupling of V1b-R directly in the pituitary, or indirectly through inhibition of hypothalamic VP and CRH output into the pituitary portal circulation. The present experiments in vitro clearly show that glucocorticoids act directly in the pituitary corticotroph. Although the data show that glucocorticoids also potentiate the stimulatory effect of other PLC-coupled hormones in the pituitary, the effects on VP are like to represent activation of the V1b receptor in the corticotroph. VP is known to interact with the oxytocin receptor (25), and oxytocin receptors are present in lactotrophs (26) and gonadotrophs (27). However, the minor effect of the oxytocin antagonist on VP-stimulated IP formation can exclude that interaction of VP with oxytocin receptors is responsible for the present observations. Because the expression of V1a receptors in the anterior pituitary is negligible (33), it is likely that most of the potentiation of VP by glucocorticoids reflects V1b-R activity in the corticotroph.
A number of sites can be identified as potential loci for the effect of glucocorticoids on VP-stimulated IP formation. Because these experiments and previous reports (18, 19) have shown down-regulation of VP receptors in the pituitary following chronic glucocorticoid administration, the site of potentiation of PLC activity must reside at the postreceptor level. Other possible mechanisms include changes in calcium channels, PLC, or the GTP-binding protein, Gq. The potentiating effect of dexamethasone pretreatment on VP-stimulated IP formation was independent of calcium in the medium during exposure of the cells to VP. Thus, it is unlikely that the potentiating effect of glucocorticoids is due to an increase in calcium channels as has been described for vascular smooth muscle cells (34).
Ionomycin is believed to stimulate PLC directly by increasing cytosolic calcium and has been used as an index of PLC activity (35). If this assumption is correct, the fact that ionomycin-stimulated IP formation was not potentiated by glucocorticoids and that potentiation of VP-stimulated IP formation occurred in spite of reductions in ionomycin-stimulated IP formation after 24 h dexamethasone pretreatment, render it unlikely that changes in PLC mediate the potentiation of the effect of VP. On the other hand, it is not possible to rule out that glucocorticoids may have differential effects in the various pituitary cell types, or that changes in phospholipase C activity occur in specific cell compartments, thus masking effects in VP-sensitive enzyme pools. While elucidation of this problem will require further studies, the specificity of the effect of glucocorticoids for ligand-stimulated IP formation suggests that the mechanism of potentiation resides at a site between the receptor and PLC, such as the GTP binding protein, Gq.
A number of studies have demonstrated that GTP binding proteins can
serve as targets for glucocorticoid regulation. The effects differ
according to the type of G protein, the tissue studied, and the
experimental conditions (in vivo vs. in vitro, time of
exposure to the steroid, etc.). For example, glucocorticoids increase
Gs in brain cortex (36) and GH3 cells (37),
but they appear to decrease Gs in aortic smooth muscle
(38). In contrast to Gs, Gi levels are under
glucocorticoid inhibition in brain cortex (36) and spleen (39), and
under stimulation in aortic smooth muscle (38). The increases in
irGq content shown in these experiments after
dexamethasone pretreatment in vivo or in vitro,
suggest that an increase in G protein is part of the mechanism by which
glucocorticoids potentiate VP-stimulated IP formation in the pituitary
corticotroph. Because corticotrophs represent 10% or less of the total
pituitary cell population (40), the marked increase in
Gq/11 probably reflects changes in other cell types in
addition to corticotrophs and is consistent with the ability of
glucocorticoids to enhance the effects of other PLC-coupled hormones
tested in these experiments (GnRH, TRH).
In other systems, it has been suggested that an elevation of Gq levels by glucocorticoids contributes to the mechanism by which glucocorticoids induce sensitization to pressor hormones such as norepinephrine, VP and Ang II (41). In vitro studies have shown that incubation of vascular smooth muscle cells with dexamethasone enhances the increase in IP formation by these hormones (42, 43), though others using a similar experimental system have reported uncoupling of the Ang II receptor by glucocorticoids (44). In contrast to the pituitary V1b-R, vascular smooth muscle Ang and V1a receptors increase after in vitro incubation with glucocorticoids (45, 46), which would also contribute to the sensitizing action of glucocorticoids.
The present demonstration that glucocorticoids increase cellular levels of Gq in the pituitary, provides a mechanism that facilitates coupling to PLC in conditions of diminished receptor number. Increased coupling of the V1b-R with PLC is likely to serve as a mechanism by which VP maintains corticotroph responsiveness in spite of elevated levels of glucocorticoids during stress (5, 47). Sensitization of the pituitary corticotroph to VP by glucocorticoids could also explain the ACTH responses to desmopressin, an antidiuretic VP agonist with low affinity for the V1b-R, described in patients with Cushing’s disease (48). In summary, the data demonstrate that glucocorticoids increase coupling of the V1b-R with PLC, an effect that is likely mediated by increases in Gq content. These findings can explain the refractoriness to glucocorticoids of VP-stimulated ACTH release and provide a mechanism by which VP facilitates corticotroph responsiveness in spite of elevated levels of plasma glucocorticoids during stress.
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Acknowledgments |
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Received February 6, 1998.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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q subfamily of guanine
nucleotide-binding regulatory protein subunits attenuate activation
of phosphatidylinositol 4,5-bisphosphate hydrolysis by hormones. J
Biol Chem 266:20519–20524 and Gi messenger RNA and
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Gs in GH3 cells. Endocrinology 121:1711–1715i immunoreactivity
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