Baker Medical Research Institute, Melbourne, Victoria 8008, Australia
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ABSTRACT |
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Two corticosteroid receptors have been cloned; they are the glucocorticoid receptor and the mineralocorticoid receptor. These receptors are members of the steroid/thyroid/retinoid receptor family of nuclear transactivating factors, which are characterized by two highly conserved zinc fingers in the central DNA binding domain, a COOH-terminal domain that encompasses the ligand binding site, and a variable NH2-terminal domain. In addition to these cloned receptors, other corticosteroid receptors have recently been identified in intestine. Steroid binding studies have identified two novel putative corticosteroid receptors in intestinal epithelia, and molecular cloning studies have detected two low-affinity receptors in small intestine that are activated by corticosteroids and induce CYP3A gene expression. This article focuses on the identification of these novel corticosteroid receptors and the potential role they may play in intestinal physiology.
intestine; mineralocorticoid receptor; glucocorticoid receptor
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INTRODUCTION |
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MINERALOCORTICOID AND GLUCOCORTICOID hormones are predominantly products of the adenal cortex and collectively are known as corticosteroid hormones. Historically, the distinctions between these steroids are based on effector criteria. For example mineralocorticoids modulate unidirectional transepithelial sodium transport, whereas glucocorticoids affect glycogen deposition in the liver. Because this early classification of steroid is based on action, it is clear that these definitions are too stringent. It is now known that glucocorticoids mediate a myriad of responses including modulating the stress response (30), immune system (26), and development (9). Mineralocorticoids, in addition to their epithelial effect on sodium transport, have nonepithelial actions including a central role in modulating salt appetite and blood pressure (20). Unlike peptide hormones and growth factors, which bind to cell surface receptors, the lipophilic nature of steroid hormones allows them to pass through the cell membrane and bind to their cognate receptor. Steroid receptors are located in the cell cytoplasm or nucleus, and on steroid binding, they undergo an allosteric change resulting in heat shock protein dissociation, receptor dimerization, and binding of the receptor to specific DNA elements, which, in turn, modulates gene transcription. Cloning of the steroid receptors provided identification of a common structure consisting of a highly conserved DNA binding domain, a COOH-terminal region that encompasses the ligand binding domain, and a variable NH2-terminal region. In addition, the recognition that the steroid receptors shared this sequence similarity with thyroid hormone receptor and retinoic acid receptor led to the concept of a nuclear receptor superfamily (15, 25). This superfamily of structurally related proteins includes receptors for steroid hormones, thyroid hormone, retinoids, vitamin D3 and fatty acids, as well as a myriad of orphan receptors for which the ligands are unknown.
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CORTICOSTEROID RECEPTORS AND SPECIFICITY |
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To date, two high-affinity receptors for corticosteroids have been
cloned: the mineralocorticoid receptor (MR), or type I corticosteroid
receptor, and the glucocorticoid receptor (GR), or type II
corticosteroid receptor. The initial distinction between these two
receptors was demonstrated in rat kidney slice studies in which
aldosterone was shown to bind with high affinity to type I sites and
with much lower affinity to type II sites. Corticosterone (the
endogenous rat glucocorticoid) had a lower affinity to both sites that
was interpreted as evidence that these were MR (17). Two
types of GR were then demonstrated in rat hippocampus; one site had
high affinity for the synthetic glucocorticoid dexamethasone, whereas
the other had a higher affinity for corticosterone and was called the
corticosterone-preferring site (11). Subsequent biochemical studies and eventual cloning of these receptors
demonstrated that the kidney type II site was the classic GR and had
high affinity for the synthetic glucocorticoid dexamethasone and the
kidney type I receptor (MR) was identical to the hippocampal
corticosterone-preferring site and intrinsically has high affinity for
both corticosterone and aldosterone. Thus MR are unique in that they
have two distinct physiological ligands, depending on the cell and
tissue in which they are expressed. In epithelial cells, or
mineralocorticoid target tissue such as kidney and colon, aldosterone
specificity is conferred on MR by 11-hydroxysteroid
dehydrogenase (11
HSD) (14, 19). The
11
-dehydrogenase activity of this enzyme converts corticosterone and
cortisol to their MR and GR inactive 11-ketometabolites, 11-dehydrocorticosterone and cortisone, and thus allows aldosterone access to MR. In tissues that express MR but do not possess
11
-dehydrogenase activity, the higher circulating levels of
endogenous glucocorticoids compared with aldosterone and the equivalent
affinity of MR for these steroids result in MR binding glucocorticoids
and mediating glucocorticoid effects (12).
Two isoforms of 11HSD have been isolated, cloned, and characterized
(1, 2). The first of these, 11
HSD1, is NADP preferring and bidirectional, although it acts predominantly as a reductase in
vivo, potentiating glucocorticoid action by forming active glucocorticoids from inactive 11-ketometabolites and thus increasing the local tissue concentration of endogenous glucocorticoids. 11
HSD1
is not present in intestinal epithelia (36). The second, 11
HSD2, operates as an exclusive 11
-dehydrogenase for endogenous glucocorticoids, and, given its colocalization with MR in
sodium-transporting epithelia and the increase in sodium retention when
enzyme activity is compromised (37, 39), it is this enzyme
that confers aldosterone specificity on MR. This isoform is present in
intestinal epithelia, with high expression in colon and ileum
(36).
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MR, GR, AND 11![]() |
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In intestinal epithelial cells, glucocorticoids appear essential
for cellular differentiation (6) and maintaining
electroneutral sodium absorption (5). In the small
intestine, there is good evidence that glucocorticoids regulate several
aspects of electrolyte transport, whereas mineralocorticoids have minor
or no effect. In contrast, in the colon, both mineralocorticoids and
glucocorticoids stimulate sodium and potassium transport
(29). In agreement with these functional studies is the
relatively high expression of GR and low expression of MR in duodenum
and jejunum and the high expression of both these receptors in colon
(36). The cellular response to endogenous corticosteroids
is dependent on many factors, two of which are receptor concentration
(7) and the presence of 11HSD (13, 18).
The low level of MR in duodenum and jejunum suggests that these
receptors may not be capable of inducing a major response. The minimal
11
HSD2 activity in these segments of the small intestine plus the
observation that corticosterone binding to MR or GR is not
significantly increased when 11
HSD2 activity is inhibited
(36) suggest that in vivo, corticosterone rather than
aldosterone binds MR. Thus the MR in duodenum and jejunum may resemble
hippocampal MR, which bind corticosterone in vivo (32) and
thus mediate physiological glucocorticoid actions (12).
MR, GR, and 11HSD2 are present in ileum and colon, and when
11
HSD2 activity is inhibited, corticosterone binding to MR increases fourfold, whereas in contrast, binding to GR only doubles
(36). These data suggest that in vivo, MR in these
intestinal segments bind aldosterone and that corticosterone binding to
GR is also modulated by enzyme activity. This is supported by
functional studies in which both mineralocorticoids and glucocorticoids
have been shown to regulate electrolyte transport in both ileum and colon (29). Given that MR have substantially higher
affinity for corticosterone than do GR, the consistently enhanced
occupancy of MR compared with GR in colon when 11
HSD2 is inhibited
cannot be explained simply on the basis of increased corticosterone
concentrations. A possible interpretation of these data is that
11
HSD2 is in much closer association with MR than with GR. This
could be due to either the fact that some colonic epithelial cells
express GR only so enzyme inhibition does not alter
corticosterone binding to GR in these cells or an intimate
intracellular association of 11
HSD2 with MR so that the local
microconcentration of corticosterone is lower for MR than GR. The
latter is supported by transfection studies in which cotransfection of
both MR and 11
HSD2 in HEK293 cells resulted in association of both
proteins with the endoplasmic reticulum membrane, which differed from
the nuclear and cytoplasmic distribution of MR when transfected alone
(27). In addition to 11
HSD2 modulating corticosteroid
responses in intestinal epithelia, other studies have demonstrated that
the cellular milieu imparts an apparent low affinity and reduced
binding capacity on colonic GR for both corticosterone and the
synthetic glucocorticoid dexamethasone (31). The
mechanisms involved are yet to be determined, although steroid
availability and an inherently lower affinity-receptor complex in
intact cells may be involved.
The combination of an apparent low affinity of corticosterone for GR
and the low intracellular concentration of this steroid due to 11HSD
activity questions the role GR plays in colonic epithelial cell
physiology. There is good evidence that synthetic steroids such as
dexamethasone and RU28362 regulate cation transport in colon via GR
(3-5), but studies using the endogenous
glucocorticoid corticosterone are limited. When endogenous
corticosteroids are removed in rats by adrenalectomy, colonic
Na+-K+-ATPase activity and electrolyte movement
are lower than in intact animals (4, 40). Colonic ion
transport is restored by the administration of low doses of
dexamethasone or RU26988 but not by physiological doses of aldosterone
(3, 4). Endogenous glucocorticoids therefore maintain
basal colonic ion-transport activity via GR. In another study on intact
animals, dexamethasone but not aldosterone increased
Na+-K+-ATPase
1-subunit mRNA
expression, an effect mimicked by 11
HSD inhibition with
carbenoxolone, indicating that the effect was mediated by endogenous
corticosterone via GR (16). The relatively low-affinity GR
in intact colonic epithelial cells and the presence of 11
HSD2
strongly suggest that levels of circulating "free" corticosterone
(~10 nM) (21) would not significantly occupy colonic GR,
even if 11
HSD activity is inhibited. The question of how endogenous
glucocorticoids mediate effects in colon is moot, although the
identification of a novel putative steroid receptor in colonic
epithelial cells, which binds 11-dehydrocorticosterone (DHB), the
11-ketometabolite of corticosterone produced by 11
HSD2 (33), may provide the answer. This putative receptor has
negligible affinity for aldosterone, dexamethasone, estradiol, RU38486,
and 5
-dihydrocorticosterone, the classic ligands for the other
members of the steroid receptor family. In addition, competitive
inhibitors of 11
HSD2 do not compete for binding, suggesting that
binding is not to this enzyme (Table 1).
The putative DHB receptor colocalizes with 11
HSD2, although not all
11
HSD2-expressing cells have the receptor, further suggesting that
the putative receptor is not 11
HSD2 (35). A
physiological function of a DHB receptor is yet to be defined, but,
given its colocalization with 11
HSD2 and the fact that it would
reflect circulating levels of endogenous glucocorticoids, it is
conceivable that the DHB receptor mediates endogenous glucocorticoid
effects in 11
HSD2-expressing cells such as colonic epithelia. Thus a
DHB receptor would allow mineralocorticoid target cells to respond to
circulating glucocorticoid without compromising the aldosterone
selectivity of MR. Consistent with the possibility that
11-dehydrocorticosterone via a DHB receptor mediates glucocorticoid
effects is the demonstration that 11-dehydrocorticosterone can regulate
cation transport in toad bladder and rat kidney (10, 28).
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NOVEL NUCLEAR CORTICOSTEROID RECEPTORS IN SMALL INTESTINE |
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In addition to GR, MR, and the putative DHB receptor, another
corticosteroid binding site has been described in epithelial cells of
the intestine (34). In duodenum and jejunum,
corticosterone binds to a nuclear localized site that has a relatively
low affinity for corticosterone (50 nM), a high capacity, and a broad
steroid specificity compared with both MR and GR (Table 1). The steroid specificity profile of this binding site distinguishes it from MR, GR,
and other classic steroid receptors (androgen receptor, progesterone
receptor, estrogen receptor), although the specificity mirrors the
potency of various steroids to inhibit 11HSD2 activity, suggesting
that binding may be to the substrate binding site on an 11
HSD
isoform. In discordance with this concept is the difference in both
tissue distribution and intracellular localization between the small
intestinal binding site and 11
HSD2 (34).
The role the small intestinal low affinity, high-capacity corticosterone binding sites play in vivo is yet to be determined, although the recent cloning of two orphan receptors expressed in the small intestine may provide insight into the function of this binding site. These orphan receptors, termed human steroid/xenobiotic receptor (SXR) (8, 24) and the rodent ortholog pregnane X receptor (PXR) (22), are activated by corticosteroids. They induce the expression of the MDR1 gene, (38) which encodes a transporter that protects cells from toxicity by rapidly effluxing drugs, and CYP3A genes (8, 22), which are important in the metabolism and elimination of xenobiotics and steroids. Therefore, PXR and SXR are implicated in both catabolism and clearance of xenobiotics and steroids from cells. These receptors respond to high concentrations of a diverse group of compounds including xenobiotics and both synthetic and endogenous steroids. The different steroid and xenobiotic CYP3A induction profiles between PXR and SXR is thought to reflect the differences in ingested nutrients and xenobiotics between the different species. The corticosterone binding site in the small intestine is similar to PXR and SXR in its broad steroid specificity, nuclear localization, and high expression in the small intestine. In contrast with these receptors is the 100-fold-higher affinity of corticosterone for the small intestinal binding site (50 nM compared with 5 µM), and steroid specificity appears to be restricted to C21 steroids. The small intestinal receptor may be related to PXR and SXR as one of a novel branch of the nuclear receptor family in which the receptors are of low affinity, high capacity, and regulate the metabolism of a broad spectrum of compounds. The physiological role of the small intestinal receptor might be more defined than that of PXR and SXR in that it would provide an intracellular environment allowing corticosteroid receptors to respond to endogenous glucocorticoids while at the same time protecting them from ligands in ingested material. A caveat in this interpretation is the absence of the small intestinal binding site in the colon, which would also be exposed to exogenous ligands. If the DHB receptor is the physiological GR in the colon, then the restricted steroid specificity of this site compared with classic GR (Table 1) may be enough to protect it from ingested ligands so a small intestinal binding site would not be required under these conditions.
In conclusion, the findings discussed here have provided
evidence for both classic (GR, MR) and nonclassic corticosteroid receptors in gut mucosa (Table 1). The relatively low-affinity, high-capacity receptors for corticosteroids (SXR, PXR) in intestine appear to regulate genes involved in both drug metabolism and efflux
from cells. Thus these receptors are probably important in protecting
gut epithelia from both ingested cytotoxic agents and ligands for the
high-affinity corticosteroid receptors. The identification of the
xenobiotics and steroids that activate these low-affinity receptors
will be significant in minimizing adverse drug effects. The low
affinity and broad steroid specificity of the small intestinal binding
site suggests that it may be related to PXR and SXR, although the more
restricted steroid specificity of this site indicates that it may have
a more specific role. The existence of a DHB receptor in
mineralocorticoid target cells is not unanticipated in that it would
explain how endogenous glucocorticoids can mediate glucocorticoid
effects in 11HSD2-expressing cells. Cloning of both the DHB receptor
and the small intestinal receptor is required to clearly identify these
binding sites as receptors and determine the role they play in
intestinal physiology.
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FOOTNOTES |
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Address for reprint requests and other correspondence: K. Sheppard, Baker Medical Research Institute, PO Box 6492, St. Kilda Rd. Central, Melbourne, Vic 8008, Australia (E-mail: karen.sheppard{at}baker.edu.au).
First published January 16, 2002;10.1152/ajpgi.00531.2001
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