Download GLUCOCORTICOID AND MINERALOCORTICOID RECEPTORS

Annu. Rev. Med. 1997. 48:231–40
Copyright © 1997 by Annual Reviews Inc. All rights reserved
GLUCOCORTICOID AND
MINERALOCORTICOID
RECEPTORS: Biology and Clinical
Relevance
John W. Funder, MD
Baker Medical Research Institute, Prahran, Australia 3181
KEY WORDS: hormone response elements, apparent mineralocorticoid excess, NFκB, AP-1,
pseudohypoaldosteronism, nonclassical receptors, 11-HSD2
ABSTRACT
Mineralocorticoid and glucocorticoid receptors act as homodimers via canonical
pentadecamer hormone response elements to regulate transcription. Glucocorticoid, but as yet not mineralocorticoid, receptors have been shown also to
modulate AP-1- and NFκB-induced transcription by direct protein-protein interactions. The role of 11β−hydroxysteroid dehydrogenase in conferring aldosterone specificity on epithelial mineralocorticoid receptors has been proven by
the demonstration of sequence mutations in all cases of apparent mineralocorticoid excess examined to date. The autosomal form of aldosterone resistance
(pseudohypoaldosteronism) has been shown to reflect loss-of-function mutations in epithelial sodium channel subunit sequence. (Patho)physiological roles
for aldosterone and glucocorticoid membrane receptors, and for the recently
described nuclear receptors for 11-ketosteroids in 11β−hydroxysteroid dehydrogenase–protected epithelia, remain to be established.
Background
The human glucocorticoid receptor (GR) was first cloned and expressed in
1985 (1) as two forms: a ligand-binding GRα of 777 amino acids; and a
742–amino acid β isoform, which differs only in the last 15 amino acids and
which does not bind active glucocorticoids. Long dismissed as a cloning
0066-4219/97/0401-0231$08.00
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artefact, GRβ are expressed at modest but varying levels in a range of tissues
and act as ligand-independent negative regulators of glucocorticoid action (2).
The cloned and expressed GRα showed high affinity for dexamethasone,
modest affinity for the physiologic steroids cortisol and corticosterone, and
low affinity for aldosterone, deoxycorticosterone, and the sex steroids, consistent with previous in vivo and in vitro studies. The human mineralocorticoid
receptor (MR), of 984 amino acids, was cloned and expressed two years later
(3). It has 57% amino acid identity with GRα in the ligand binding domain
(LBD), and 94% in the DNA binding domain (DBD). The cloned and expressed MR showed high and equivalent affinity for corticosterone, aldosterone, and cortisol, confirming previous studies on MR in rat kidney and
hippocampus (4); subsequently, MR have been shown in addition to have
equivalent high affinity for progesterone (5).
Progesterone receptors (PR) and androgen receptors (AR) show significant
amino acid homology (LBD, ∼50%; DBD, ∼90%) with MR and GR. Together,
these four receptors constitute a subfamily within the steroid/thyroid/retinoid/
orphan receptor (STRO) superfamily, which currently lists over 150 members
(6). In common with estrogen receptors but in contrast with other STRO
superfamily members, MR/GR/PR/AR in the unliganded state are associated
with a complex of chaperone proteins, including the heat shock protein Hsp 90
and the immunophilin Hsp 56, which maintain the receptors in an inactive
form with high affinity for hormone. Upon appropriate ligand binding, the
associated chaperone proteins are shed, exposing nuclear localization signals
in MR and GR, which are thus enabled to access and be retained in the
nucleus.
MR and GR as Transcription Factors
Reflecting the high degree of homology within their DBD, MR/GR/AR/PR
bind to common nuclear hormone response elements (HRE), with a consensus
15-nucleotide sequence of AGAACAnnnTGTTCT. Regulation of transcription is dependent on interaction not only with the HRE, but also with the
transcription initiation complex, an assembly of transcription factors and RNA
polymerase II. In addition, largely from studies of other members of the STRO
superfamily, there is increasing evidence for the existence of coactivators,
which act as bridging factors between activated receptor and the transcription
initiation complex (7), and similarly for the existence of corepressors, both
ligand-dependent (8) and -independent (9).
Perhaps not surprisingly, given the inverted palindrome sequence of HRE,
members of the MR/GR/PR/AR subfamily appear to act as dimers, either
homodimers or heterodimers. For MR and GR, heterodimers have been reported to enhance (10) or lower (11) transcriptional activity, a difference
GR AND MR, BASIC AND CLINICAL
233
probably reflecting the number of HRE used in the reporter constructs. There
is also in vitro evidence for heterodimerization of MR and GR with the A form
of PR (12, 13). Given the essentially ubiquitous distribution of GR, such
heterodimers would not be unexpected in MR- or PR-containing cells; the in
vivo occurrence and physiologic relevance of such heterodimers, however, are
yet to be established.
Distinguishing GR- and MR-Mediated Responses
In in vitro cotransfection systems, GR and MR appear to have equivalent
transcriptional activity at a classical (canonical) HRE when activated by an
appropriate ligand (14); moreover, MR are equivalently activated by cortisol
and aldosterone in some studies (14), although others (15) have claimed aldosterone to be more potent, equivalence in affinity notwithstanding. There are
clear-cut physiological and clinical differences in mineralocorticoid and glucocorticoid action, however, suggesting that in vivo mechanisms other than those
established in MR/GR HRE cotransfection studies operate to ensure specificity.
To date, no unambiguously specific mineralocorticoid response elements
have been demonstrated, despite an intensive search in appropriate aldosterone
target tissues. The recent demonstration of the aldosterone-selective increase
in expression of the γ-subunit of the epithelial Na+ channels (16) may allow a
more focused exploration of this area, although in unpublished reports MR
knockout (MRKO) mice show normal amiloride-sensitive Na+ channel activity (TJ Cole, personal communication). In fact, specific mineralocorticoid
response elements may be more profitably sought in MR-regulated genes in
nonepithelial tissues rather than classical aldosterone target tissues, as discussed in detail below.
At the HRE level, one distinction between MR and GR is the ability of the
latter to self-synergize, i.e. to produce more than additive effects via multiple
HRE, an N-terminal–dependent phenomenon; MR share <15% sequence identity in this region and do not self synergize (17, 18). A second difference is the
ability of GR, but not MR, to inhibit induction of AP-1–dependent genes by
Fos-Jun heterodimers (14). This is not an isolated interaction, in that GR and
Jun-Jun homodimers clearly synergize rather than mutually repress (19);
whether or not MR-specific heterodimer formation with other transcription
factors underlies the MR-specific actions in nonepithelial tissues, for example,
awaits exploration.
Glucocorticoids affect the transcriptional activity of NFκB, another very
important mediator of the inflammatory response, in at least two ways. First,
GR, via a classical genomic action, increase the levels of 1κB, which traps
NFκB in the cytoplasm (20, 21). Second, GR interact with p65, one of the
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transcriptionally active subunits of NFκB, by a protein:protein interaction
similar to that for Fos-Jun (22). The evidence for such protein:protein interactions being independent of the genomic actions of GR is strong, in that the
effects on both NFκB- (23) and AP-1–dependent genes (24) are seen with
transactivation-deficient GR mutants.
To date, the clearest evidence for MR-specific interactions comes from
studies on isolated neonatal cardiomyocytes (25), where activation of MR by
aldosterone increases [3H]leucine incorporation, whereas activation of GR by
dexamethasone predictably lowers incorporation. Activation of protein kinase
C in response to increased medium glucose lowers the threshold and increases
the MR response to aldosterone, but it has no effect on the GR response; the
mechanisms underlying this selective synergy are yet to be explored.
Epithelial and Nonepithelial MR
MR not only have equivalent affinity for aldosterone and cortisol, they are also
expressed at considerable levels in tissues such as hippocampus and heart (1,
26), which are not classical aldosterone targets. The question of how aldosterone can occupy MR in epithelial target tissues has been answered, at least
in part, by the recent cloning and expression of the enzyme 11β-hydroxysteroid dehydrogenase 2 (11-HSD2) from human kidney (27), and by the demonstration of a range of mutations in all cases of the syndrome of apparent
mineralocorticoid excess studied to date (28–30).
As shown in Figure 1, in epithelial aldosterone target tissues, cortisol is
normally excluded from both MR and GR by the operation of 11-HSD2, which
can be inhibited by licorice or carbenoxolone ingestion. Aldosterone is not a
substrate for 11-HSD2, because its 11-OH group is protected by cyclization
with the unique aldehyde group at C18 to yield a very stable 11,18 hemiketal.
If the enzyme is blocked or deficient, cortisol can occupy MR (for which it has
∼10-fold higher affinity than for GR) and mimic the aldosterone effect on ion
transport. Importantly, from studies using the GR-specific agonist RU28362,
activation of GR in these cells is followed by effects on ion flux indistinguishable from those of aldosterone via MR (31, 32), strong evidence for an action
via a nondiscriminating HRE.
In nonepithelial tissues MR, although apparently the same gene product,
differ operationally in a number of ways. Figure 2 depicts the actions of MR in
the circumventricular region of the brain and their role in blood pressure
elevation in response to aldosterone. Such MR are not protected and therefore
are not aldosterone-selective. Also, when they are occupied by aldosterone,
given either intracerebroventricularly or systemically in rat studies (33, 34),
blood pressure rises. Corticosterone, the physiologic glucocorticoid in the rat,
is not an MR agonist as it is in the kidney (32) but blocks the effect of
GR AND MR, BASIC AND CLINICAL
235
Figure 1 A renal cortical–collecting tubule cell containing mineralocorticoid receptors (MR),
glucocorticoid receptors (GR), and 11β-hydroxysteroid dehydrogenase (11-HSD2). Cortisol (and
corticosterone) can bind with high affinity to both MR and GR, and aldosterone can bind only to
MR. Normally, cortisol (F) is metabolized by 11-HSD2 to receptor-inactive cortisone (E). If
11-HSD2 activity is reduced congenitally, by licorice ingestion or by carbenoxolone administration,
F can activate MR and GR and, in either case, has indistinguishable effects on urinary electrolyte
fluxes (31, 32). The ability of GR to mimic the effects of MR suggests that the action of both receptors
is mediated by a relatively nondiscriminating hormone response element (HRE). The direction of
the arrows refers to urinary ionic content and not transepithelial ion flux.
coinfused aldosterone. The GR-specific agonist RU26988 infused intracerebroventricularly neither blocks or mimics the aldosterone response, evidence
for MR-specific actions distinct from those of GR, again in contrast with the
demonstrated equivalence of MR and GR on renal ion fluxes (31, 32). Finally,
intracerebroventricular infusion of the MR-selective antagonist RU28318 can
block the central hypertensive action of peripherally infused aldosterone, with
no change in various indices of peripheral aldosterone action (35, 36).
Other nonepithelial MR-mediated effects of aldosterone have been described, most notably in producing experimental cardiac hypertrophy and fibrosis (37). Like the central effects of aldosterone on blood pressure, these
effects are mediated via unprotected MR and are blocked rather than mimicked
by corticosterone occupancy of MR (38). The extent to which this mechanism
may be operant in the cardiac fibrosis of congestive cardiac failure has yet to
be established.
Steroid Resistance Syndromes
Over the last 15 years, sporadic and familial cases of glucocorticoid resistance,
manifest as hypertension and hyperandrogenization, have been reported; in the
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Figure 2 Circumventricular neuron–containing mineralocorticoid receptors (MR). MR activation
by aldosterone (A) leads to blood pressure (BP) elevation; MR occupancy by corticosterone/cortisol
(C), or by the MR antagonist RU28318 (RU), is without agonist effect but blocks the action of
aldosterone (33, 35). The findings that neither agonist nor antagonist effects via MR are mimicked
or blocked by glucocorticoid receptor occupancy is interpreted as evidence for MR action via a
specific mineralocorticoid response element (MRE), as opposed to the nonselective hormone
response element in the classical epithelial aldosterone target tissue shown in Figure 1.
majority of these cases, GR mutations have been established as the molecular
basis for the syndrome (39–41). More recently, in a study of over 200 nonselected subjects given a dexamethasone suppression test, a relatively high incidence (∼10%) of allelic variation was found, with the majority having a variant
consistent with some degree of glucocorticoid resistance (42). Mineralocorticoid resistance was first described in 1958 (43) in association with pseudohypoaldosteronism (PHA); subsequently, sporadic and autosomal recessive cases
have been documented, and reduced or absent MR in peripheral mononuclear
leucocytes have been described (44). On the other hand, in neither the sporadic
nor the more seriously affected familial form could any MR coding abnormality be established, despite exhaustive studies on three continents (45–47).
Recently, linkage analysis of family members in kindred with the autosomal
recessive form of PHA provided no evidence for involvement of the region of
chromosome 4 containing the MR gene (48); even more recently, the defect in
such patients was shown to be a loss-of-function mutation in sodium channel
subunits (i.e. the opposite of Bartter’s syndrome) (49). The mechanisms of MR
down-regulation in this severe form of PHA and whether an MR defect is
primary in sporadic cases have not yet been resolved.
Considerable insight into steroid resistance syndromes—and perhaps into
aspects of steroid action, including, for example, MR:GR heterodimers—can
GR AND MR, BASIC AND CLINICAL
237
be expected from the recent production of GRKO and MRKO mice. Homozygous (−/−) GRKO mice are born at the expected Mendelian frequency, but
they usually die within hours of birth of atelectasis. A minority, however,
survive, showing very high levels of adrenocorticotropin and corticosterone
(50). Heterozygous (+/−) GRKO mice show adrenocorticotropin and corticosterone levels intermediate between those of −/− homozygotes and wild type.
These latter data suggest that normal GR levels are necessary to maintain a
normal set of the pituitary-adrenal axis. On the other hand, heterozygotes show
normal adrenal medullary development, in contrast with −/− homozygotes in
which the adrenal medulla is vestigial, and the glucocorticoid-regulated enzyme PNMT, which catalyzes the conversion of epinephrine to norepinephrine, is not expressed. MRKO mice have been produced (TJ Cole, personal communication), again at expected Mendelian ratios after heterozygote
matings, but they lose weight from approximately four days postpartum and
die on days 8–11, presumably reflecting their inability to retain sodium and its
relatively low content in milk. Further studies characterizing the MRKO
mouse are currently in progress.
Non-MR, Non-GR Corticosteroid Receptors
The demonstration of rapid hormone effects with a time course inconsistent
with genomic action suggests that through physiologic mineralocorticoids and
glucocorticoids additional sites may exist. For glucocorticoids, at least, the
demonstration of a range of protein:protein interactions involving classical GR
should serve as a caution against overinterpreting rapid time-course data. For
both glucocorticoids and mineralocorticoids, however, additional specificity
data support actions via other than classical receptors.
In the amphibian, corticosterone has been shown to have high potency in
rapidly extinguishing the clasp reflex and to bind with nanomolar affinity to
neuronal membrane preparations; the rank order of in vivo potency is well
correlated with the ability to displace labeled corticosterone from the membranes, with dexamethasone and RU28362 having low potency on either index
(51). Aldosterone has similarly been shown to have very rapid effects on ion
fluxes in a variety of cells, an effect that is not spironolactone-inhibitable and
that clearly occurs via receptors other than the classical MR (52). In both
instances, however, isolation and characterization of the putative membranebound receptors have proven elusive.
Very recently, evidence for the existence in aldosterone-target tissues of a
classical intracellular receptor specific for 11-keto steroids has been reported
(53). Given the exclusion of glucocorticoids from both MR and GR in such
tissues by their conversion to their 11-keto congeners, such a receptor would
represent a mechanism for physiologic actions of circulating glucocorticoids
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on aldosterone target tissues. More detailed characterization should be possible if the receptor can be cloned and expressed; its presence in GRKO mice
would appear to exclude GRβ from such a role.
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