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Endocrinology Vol. 143, No. 10 3796-3801
Copyright © 2002 by The Endocrine Society

ARTICLE

Posttranslational Modulation of Glucocorticoid Feedback Inhibition at the Pituitary Level

Min Chin Lim, Michael J. Shipston and Ferenc A. Antoni

Medical Research Council Brain Metabolism Unit, Department of Neuroscience (M.C.L., F.A.A.), and Membrane Biology Group, Section of Biomedical Sciences (M.J.S.), University of Edinburgh, Edinburgh, Scotland, United Kingdom EH8 9JZ

Address all correspondence and requests for reprints to: Dr. F. Antoni, Department of Neuroscience, University of Edinburgh, Edinburgh, Scotland, United Kingdom EH8 9JZ. E-mail: ferenc.antoni{at}ed.ac.uk.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Diagnostic tests of hypothalamic-pituitary-adrenocortical function in psychiatric illness largely report the interaction of hypothalamic secretagogues with glucocorticoids at the pituitary level. This study investigated whether the efficiency of glucocorticoid inhibition is subject to modulation by intracellular processes that enhance cAMP accumulation and/or facilitate membrane depolarization. The secretion of ACTH induced by corticotropin-releasing factor (CRF; 0.1 nM) in primary cultures of rat anterior pituitary cells was markedly inhibited upon a 2-h exposure to 100 nM corticosterone. Arginine vasopressin (2 nM) enhanced the cAMP as well as the ACTH responses to CRF and reduced the efficiency of glucocorticoid inhibition of ACTH release. The action of arginine vasopressin was mimicked by rolipram, an inhibitor of cyclic nucleotide phosphodiesterase type 4. Application of the broad specificity K+ channel blockers clofilium and astemizole produced minor or no significant enhancement of CRF-induced ACTH release, respectively, but opposed the inhibitory effect of corticosterone. Specific blockers of HERG, KCNQ, and Isk channels had no effect on ACTH release under any condition examined. In summary, these data reveal multiple sites of posttranslational modulation of adrenal corticosteroid action at the level of the pituitary gland, which appear important for the outcome of diagnostic tests of hypothalamic-pituitary- adrenocortical function.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
CORTICOSTEROID feedback inhibition of the hypothalamic-pituitary-adrenocortical (HPA) axis is a key process in the maintenance of body homeostasis (1, 2). It is well established that the anterior pituitary corticotrope cell is a pivotal target of corticosteroid feedback (3, 4). Diagnostic tests of HPA axis function in major psychiatric disorders essentially report secretagogue-glucocorticoid interaction at the anterior pituitary corticotrope cell (5, 6). The cellular mechanisms underlying corticosteroid feedback action remain to be clarified (3, 4, 7). Previous studies of rat anterior pituitary tissue and the mouse corticotrope tumor cell line AtT20 in vitro have helped to delineate a model of glucocorticoid inhibition of corticotropin releasing-factor (CRF)- induced ACTH release (3, 4). In AtT20 cells, CRF inhibits large conductance Ca2+-activated K+ channels (BK channels) through protein kinase A, resulting in sustained depolarization and enhanced exocytosis (8). Protein(s) rapidly (30 min) induced by glucocorticoids enhances protein phosphatase activity in the vicinity of BK channels and thus blocks the action of protein kinase A (9). As a result, intracellular free Ca2+ transients are clamped at levels that activate the stress hormone regulated BK channel variant expressed in AtT20 cells (10), but are insufficient for substantially enhanced secretory activity (11). The nature of the rapidly induced protein(s) remains unclear; current candidates include annexin I (7) and dex-ras 1 (12).

Several physiological studies indicate that the efficiency of glucocorticoid feedback inhibition undergoes plastic changes depending on the stressor stimulus. For example, glucocorticoid feedback inhibition of plasma ACTH levels was not apparent in rats subjected to hemorrhage (13). In rats with chronic autoimmune inflammation, exaggerated and prolonged increases in plasma corticosteroids are vital for survival and involve a resetting of the negative feedback effect on the HPA axis (14, 15). In humans, strenuous exercise gives rise to a dexamethasone nonsuppressor phenotype (16, 17). A common feature of all of the aforementioned paradigms is activation of the hypothalamic vasopressinergic neurosecretory system (18). Indeed, several groups have reported that rat pituitary cells exposed to high, nonphysiological levels of arginine vasopressin (AVP) showed signs of markedly reduced glucocorticoid feedback (19, 20, 21). Escape from dexamethasone inhibition upon injection of lysine vasopressin has also been reported in humans (22). The present study investigated the hypothesis that physiological levels of AVP are sufficient to bring about glucocorticoid resistance at the pituitary level in vitro. Furthermore, pharmacological tests were carried out to delineate the possible mechanism(s) of action of AVP and corticosterone. The data demonstrate that physiological levels of AVP in combination with CRF induce glucocorticoid resistance of stimulated ACTH release. The reduction of glucocorticoid inhibition correlated with the magnitude of the cAMP response induced by the secretagogues. Finally, clofilium and astemizole, which are blockers of several recently characterized K+ channels, also reversed the inhibitory action of corticosterone, but had no apparent effect on cAMP accumulation. Taken together, the data reveal multiple sites of posttranslational modulation of corticosteroid action at the level of the pituitary gland, which appear important for the outcome of diagnostic tests of HPA function.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Reagents
Reagents for tissue culture and RIAs were previously described (23). Synthetic human 41-amino acid residue CRF and AVP were obtained from Bachem (St. Helens, UK). Astemizole was purchased from Sigma-Aldrich (Gillingham, UK). Clofilium tosylate was obtained from RBI (Sigma, Poole, UK). The following compounds were generously provided by the manufacturers: Rolipram—Schering AG (Berlin, Germany); E4031—Eisai Chemical Co. Ltd. (Kashima-gun, Ibaraki-ken, Japan); dofetilide (UK-68,798)—Pfizer Central Research (Sandwich, UK); WAY-123,398—Wyeth-Ayerst Research (Princeton, NJ); and chromanol 293B—Hoechst-Marion (Frankfurt/Main, Germany).

Cell cultures
Dispersed rat anterior pituitary cells were prepared from the pituitary glands of male Wistar rats (30–40 d postnatally; Charles River Ltd., Margate, UK) as previously described (23). Approximately 5 x 104 cells/well were plated in 24-well tissue culture plates (Falcon, B&D, Le Point de Claix, France) and cultured in DMEM containing 2.5% fetal bovine serum (Harlan-Sera-lab, Belton, Loughborough, UK) and 7.5% horse serum (Sigma, H-1138). Monitoring of the ACTH response to various stimuli was as detailed previously (23). Briefly, corticosterone or vehicle was applied in fresh, serum-free medium 2 h before stimulation with CRF. Blockers of K+ channels were applied 30 min before and during the 60-min incubation with CRF. In some experiments cellular cAMP content was also measured. The cells were pretreated as described for ACTH release, and the incubation was terminated by aspiration of the medium, immediately followed by the addition of 0.1 M HCl. Cellular cAMP was extracted into 0.1 M HCl by repeated freeze-thawing, acetylated, and quantified by RIA (24).

Data analysis
Data were evaluated by one- or two-way ANOVA, followed by multiple comparisons as appropriate. Results presented as a percentage of control ACTH release were derived from the raw data according to the formula: (X - B)/(C - B) x 100%, where X is the value analyzed, B is the basal ACTH secretion, and C is the amount of ACTH observed in the presence of a control stimulus.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Vasopressin (2 nM) enhanced the response to CRF (0.1 nM), but failed to stimulate ACTH when given alone (Fig. 1AGo). Pretreatment with corticosterone produced a dose-dependent inhibition of CRF-induced ACTH release (Fig. 1BGo). The efficiency of this inhibition was markedly reduced by AVP. The cAMP phosphodiesterase inhibitor rolipram mimicked the effects of AVP on the ACTH response as well as its inhibition by corticosterone (Fig. 2Go). AVP enhanced the cAMP response to CRF at both 10 and 60 min (Fig. 3AGo). A series of similar studies with various CRF and AVP concentrations revealed that the ability of 100 nM corticosterone to suppress ACTH secretion markedly diminished as the agonist-evoked cAMP response increased (Fig. 3BGo).



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  		Figure 1. AVP reduces the efficiency of glucocorticoid feedback inhibition. A, ACTH response elicited by 0.1 nM CRF and 2 nM AVP. Columns represent means; bars indicate the SEM (n = 4/group). The effect of CRF was significant (P < 0.01), and there was a significant (P < 0.05) interaction between CRF and AVP (by two-way ANOVA). B, Concentration-dependent inhibition of 0.1 nM CRF-evoked ACTH release by corticosterone in the absence and presence of 2 nM AVP. Data are expressed as a percentage of the net ACTH release evoked by the respective control stimulus. Values are the mean ± SEM (n = 4/group). *, P < 0.05 compared with corresponding vehicle-treated group by one-way ANOVA, followed by Dunnett’s test. Results shown are representative of eight experiments.

 


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  		Figure 2. The cyclic nucleotide phosphodiesterase inhibitor rolipram mimics the effects of AVP. A, ACTH response to 0.1 nM CRF and 0.1 mM rolipram (Roli). Solid columns indicate means; bars indicate the SEM (n = 4/group). The effect of CRF was significant (P < 0.01), and there was a significant (P < 0.05) interaction between CRF and rolipram by two-way ANOVA. B, Concentration-dependent inhibition of 0.1 nM CRF-evoked ACTH release by corticosterone in the absence and presence of 0.1 mM rolipram. Data are expressed as a percentage of the net ACTH release evoked by the respective control stimulus. Values are the mean ± SEM (n = 4/group). *, P < 0.05 compared with corresponding CRF group by one-way ANOVA, followed by orthogonal contrasts. Results shown are representative of four experiments.

 


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  		Figure 3. Intracellular cAMP levels are a principal determinant of the efficiency of glucocorticoid feedback inhibition. A, Potentiation of the cAMP response to CRF by AVP. Columns are the means; bars indicate the SEM (n = 4/group). The basal cAMP level measured at time zero was 153.11 ± 7.44 fmol/well. The effect of CRF was significant (P < 0.01) at both time points, and there was a significant (P < 0.05) interaction with AVP at both time points by two-way ANOVA. B, The degree of inhibition of stimulated ACTH secretion by 100 nM corticosterone plotted against the intracellular cAMP levels measured at 60 min. CRF or CRF and AVP in combination were used. The numbers indicate the nanomolar concentrations of the respective secretagogues. Data points are the average of four determinations.

 
Plasma membrane K+ channels are prominent targets of cAMP-dependent phosphorylation (25) and have been previously implicated in the action of glucocorticoids in corticotrope cells (8) as well as in hippocampal pyramidal neurons (26, 27). As previous results with the blocker tetraethylammonium (23) excluded the involvement of a number of well characterized K+ channels in glucocorticoid action in our experimental system, the class III antiarrhythmic agent clofilium and the antihistamine drug astemizole were tested. These drugs are blockers of HERG, KCNQ, and IsK type channels, all of which are expressed in pituitary cells (28). Both agents significantly reduced the efficiency of glucocorticoid inhibition, (Fig. 4Go), but when applied above 10 µM inhibited CRF-induced ACTH release (not shown) and thus were not tested further at concentrations higher than 10 µM. Most notably, 10 µM astemizole was without effect on basal and CRF-induced ACTH release (Fig. 5AGo), but markedly reduced the inhibitory effect of up to 1 µM corticosterone (Fig. 5BGo). Clofilium modestly enhanced the ACTH response to CRF and also reduced the ability of corticosterone to inhibit CRF-stimulated ACTH release (Fig. 5Go, C and D) Importantly, neither drug altered the cAMP response to 0.1 nM CRF at 10 or 60 min (not shown), suggesting that the site of action is downstream of cAMP. The involvement of potential targets of clofilium and astemizole, namely, HERG-, KCNQ-, and Isk-type channels, was addressed by applying the selective blockers E4031, dofetilide, WAY-123,398 (all at 1–10 µM), and chromanol 293B (5–50 µM), respectively. None of these drugs had a statistically significant effect on basal or CRF-induced ACTH release, and there was also no alteration of the inhibition of 0.1 nM CRF-induced ACTH release by 100 nM corticosterone (data not shown).



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  		Figure 4. Clofilium and astemizole attenuate the inhibition of CRF-stimulated ACTH release by 100 nM corticosterone. The effects of clofilium (A) and astemizole (B) on basal ({circ}) or 0.1 nM CRF-evoked ACTH release in the absence ({bullet}) and presence ({blacktriangleup}) of 100 nM corticosterone (CORT) pretreatment are shown. Data are expressed as a percentage of the net ACTH release evoked by the respective control stimulus. Values are the mean ± SEM (n = 3–7/group). *, P < 0.05 compared with corresponding stimuli in the absence of clofilium or astemizole. Where error bars are not visible, the SEM is less than the space required for the symbol. Results shown are representative of three and two experiments for A and B, respectively.

 


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  		Figure 5. Efficiency of corticosterone feedback inhibition is reduced by astemizole and clofilium. A, ACTH response to 0.1 nM CRF and 10 µM astemizole (AST). Solid columns are means; bars indicate the SEM (n = 3–5/group). *, P < 0.05 compared with basal by one-way ANOVA, followed by Newman-Keuls test. B, Inhibition of 0.1 nM CRF-evoked ACTH release by corticosterone in the absence and presence of 10 µM astemizole (n = 4–5/group). *, P < 0.05 compared with corresponding CRF group by one-way ANOVA, followed by orthogonal contrasts. The results shown are representative of four experiments. C, ACTH response to 0.1 nM CRF and 10 µM clofilium (CLOF). Solid columns are means; bars indicate the SEM (n = 4–5/group). *, P < 0.05 compared with basal; #, P < 0.05 compared with CRF (by one-way ANOVA, followed by Newman-Keuls test). D, Corticosterone inhibition of 0.1 nM CRF-evoked ACTH release in the absence and presence of 10 µM clofilium (n = 4–5/group). *, P < 0.05 compared with the corresponding CRF group by one-way ANOVA, followed by orthogonal contrast of means. Results shown are representative of three experiments.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
These data demonstrate that the agonist-induced cAMP response is a major determinant of the outcome of early gene induction by glucocorticoids. Furthermore, they raise the possibility that novel plasma membrane K+ channels mediate corticosteroid negative feedback in anterior pituitary corticotrope cells. Collectively, the results highlight the potential for posttranslational modulation of the negative feedback action of adrenal corticosteroids at the pituitary level.

The idea that AVP reduces glucocorticoid feedback was previously proposed (see Ref. 18 for review). However, the issue has not been addressed directly using physiological levels of secretagogue and by examining the effect of a range of corticosteroid concentrations. In a similar in vitro model Vale and co-workers (29) showed that the efficiency of inhibition of ACTH release by a 16-h exposure to dexamethasone was dependent on the size of the stimulus: ACTH release induced by 0.01–0.1 nM CRF was significantly more suppressed than that evoked by 1–100 nM CRF. Further in vitro studies reported reduced inhibition of ACTH release upon the introduction of AVP with CRF compared with CRF alone, but the concentrations of the neuropeptides were grossly pharmacological (20, 21). The present study shows for the first time, using physiologically relevant concentrations of CRF as well as AVP, that AVP induces resistance to corticosterone feedback inhibition.

The level of CRF in pituitary portal plasma is maximally 0.3 nM; at this concentration corticotropes are far from maximally stimulated. In vivo, further enhancement of the hypothalamic drive is achieved by AVP, which is copackaged and cosecreted with CRF in parvicellular hypophysiotropic neurons of the hypothalamic paraventricular nuclei (18, 30, 31, 32). In addition, there is evidence that AVP is released into hypophysial portal blood by the anatomically distinct vasopressinergic magnocellular neurons of the supraoptic and hypothalamic paraventricular nuclei, which do not synthesize CRF (see Ref. 18 for review). The synthesis of AVP by parvicellular cells has been shown to change dramatically in animal models; for example, chronic stress produces marked increases in AVP synthesis with little or no change in CRF (18, 33). The level of AVP in the hypophysial portal blood of various species ranges between 0.3 and 2 nM (18). Somewhat lower, up to 0.4 nM levels have been reported for human inferior petrosal sinus blood (34). Thus, the concentration of AVP used in the present study represents the upper extreme of the physiological range, characteristic of magnocellular activation (e.g. hemorrhage) or a state of enhanced parvicellular AVP synthesis.

Postmortem analysis of the hypothalamus of patients with depression indicated an increased degree of coexpression of CRF and AVP in the PVN (35). Similar findings were reported with aging (36), which is also characterized by a reduced sensitivity toward glucocorticoid feedback inhibition (37, 38). Acute paradigms, which have indicated an association of dexamethasone nonsuppression in humans with elevated plasma AVP, were listed in the introduction. Taken together, these studies have provided evidence that AVP counteracts glucocorticoid feedback in humans.

The principal mode of action of AVP in corticotroph cells is amplification of the cAMP response to CRF through protein kinase C (18, 39). The enhancement of the cAMP response to low physiological concentrations of CRF by AVP is dramatic, up to 10- to 15-fold in the physiological range, and is characterized by acute plastic changes in the cAMP signaling cascade (40, 41). The augmentation of CRF-induced ACTH release by AVP is modest by comparison with the enhancement of the cAMP response. Thus, it is reasonable to suggest that amplification of the CRF-evoked cAMP has downstream targets other than CRF-evoked exocytosis. Indeed, the present study shows directly that the efficiency of glucocorticoid feedback on stimulated ACTH release is inversely related to the secretagogue-induced cAMP response.

The finding that exaggerated cAMP accumulation and consequently augmented activation of protein kinase A can override glucocorticoid inhibition is in agreement with the hypothesis that glucocorticoid feedback action is mediated by a protein phosphatase that opposes the action of protein kinase A (42). Plasma membrane K+ channels are common targets of protein kinase A and glucocorticoid inhibition (8, 23). In AtT20 and transfected HEK293 cells, glucocorticoids modulate the activity of a protein phosphatase in the vicinity of the STREX variant BK channel to counteract protein kinase A stimulated by CRF-induced cAMP (42, 43). In rat anterior pituitary cells, depolarization of the membrane potential abrogated glucocorticoid feedback inhibition of stimulated ACTH release (3, 23, 44), which is consonant with the hypothesis that feedback is mediated by plasma membrane K+ channels. However, no evidence for the involvement of BK or other tetraethylammonium-sensitive K+ channels could be demonstrated in cultured rat anterior pituitary cells (23). The findings with clofilium and astemizole presented here suggest that atypical, as yet uncharacterized plasma membrane K+ channels may mediate glucocorticoid feedback inhibition in cultured rat anterior pituitary corticotropes. Specific blockers of HERG-, KCNQ-, and Isk-type K+ channels, all of which are reportedly expressed in the adenohypophysis (28), failed to alter the effect of corticosterone. It is of note that the concentration of astemizole required to oppose glucocorticoid inhibition was similar to that required for the blockage of store-operated Ca2+ channels (SOCs) in GH3 pituitary tumor cells (45). Intriguingly, dofetilide was inactive in this respect, similar to the present findings (45). It is not immediately obvious how SOCs would be important for early inhibition by glucocorticoids. However, Ca2+ entry via SOC could be intricately linked to subplasmalemmal changes in intracellular Ca2+ and could be important for the activity of Ca2+-activated K+ channels that mediate glucocorticoid feedback inhibition (26, 27, 46). Clofilium as well as astemizole inhibit more than one type of K+ channel (47, 48, 49, 50). Thus, it cannot be excluded that their action to oppose glucocorticoid feedback is due to generalized depolarization, which is known to reduce the efficiency of glucocorticoid inhibition (3, 23).

In summary, these data show that the efficiency of corticosteroid feedback inhibition may be markedly modified by agents acting on the cellular targets of glucocorticoid- induced proteins. A fundamental determinant of the efficiency of feedback inhibition is the magnitude of the cAMP response evoked by hypothalamic secretagogues. Finally, whether the observed effects of clofilium and astemizole on glucocorticoid feedback are clinically relevant requires further investigation.


   Acknowledgments
 
The generous provision of potassium channel blockers [chromanol 293B—Dr. U. Gerlach (Marion-Hoechst, Frankfurt/Main, Germany); E4031—Ms. T. Nakano (Eisai, London, UK); dofetilide—Mrs. C. Pitcher (Pfizer, Sandwich, UK); WAY-123,398—Ms. Melanie Boyd (Wyeth Laboratories, Maidenhead, UK); and rolipram—Dr. H. Wachtel (Schering AG, Berlin, Germany)] is gratefully acknowledged. We thank Prof. P. J. Lowry (University of Reading, Reading, UK) for the supply of sheep anti-ACTH serum, and the Scottish Antibody Production Unit for antisheep IgG serum.


   Footnotes
 
This work was supported by the Medical Research Council, United Kingdom, and the Wellcome Trust.

Abbreviations: AVP, Arginine vasopressin; CRF, corticotropin- releasing factor; HPA, hypothalamic-pituitary-adrenocortical; SOC, store-operated Ca2+ channel.

Received May 7, 2002.

Accepted for publication June 4, 2002.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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