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Molecular Endocrinology 20 (7): 1471-1478
Copyright © 2006 by The Endocrine Society

Minireview

The Evolution of Mineralocorticoid Receptors

Xiao Hu and John W. Funder

St. Louis Laboratories (X.H.), Pfizer Global Research and Development, St. Louis, Missouri 63017; and Prince Henry’s Institute of Medical Research (J.W.F.), Clayton, Victoria 3168, Australia

Address all correspondence and requests for reprints to: John W. Funder, Prince Henry’s Institute of Medical Research, Clayton, Victoria 3168, Australia.


   ABSTRACT
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 ABSTRACT
BACKGROUND
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 DISCUSSION
 HYPOTHESES
 ENVOI
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When the human mineralocorticoid receptor (hMR) was cloned and sequenced by the Evans laboratory, its close homology with the human glucocorticoid receptor (hGR) was noted; subsequently, on the basis of its higher sequence similarity to the GR than to the progesterone receptor (PR) or androgen receptor (AR), MR and GR have commonly been considered to share an immediate common ancestral "corticoid receptor." When, however, homology is determined for the full-length receptor, or helices 3/4/5/12, MR is least like any of the other three receptors; for the ligand binding domain, AR is clearly the least homologous. When relative binding and activation capacity of a broad panel of LXXLL cofactor peptides are compared by mammalian two-hybrid assay, GR and PR show a highly similar profile, interacting with many of the 39 peptides, with MR and AR binding very few, supporting a close functional homology between PR and GR. In addition, recent studies by He et al. on FXXLF binding by GR and PR mutants suggest that these two receptors may be closer to AR than to MR. The sequence and transcriptional activity of the S810L mutant reported by Geller et al. can be interpreted as supporting MR as being closer than GR/PR/AR to estrogen receptor/retinoid X receptor, and thus potentially the first rather than the last branch from a common MR/GR/PR/AR ancestor. On the basis of these studies together, we propose reconsideration of the evolutionary tree for the MR/GR/PR/AR subfamily, with MR closest to the primordial ancestral receptor, GR/PR sharing a common immediate ancestor, and a higher degree of evolutionary drift in the AR ligand binding domain to accommodate C19 rather than C21 steroids as physiological ligands.


   BACKGROUND
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 ABSTRACT
 BACKGROUND
RECONSIDERATION: SEQUENCE
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 DISCUSSION
 HYPOTHESES
 ENVOI
 REFERENCES
 
FOR ALMOST 20 yr, it has been assumed that mineralocorticoid receptors (MR) and glucocorticoid receptors (GR) share an immediate common ancestor. This is not surprising, given the equivalently high affinity of MR for aldosterone and the physiological glucocorticoids cortisol and corticosterone (1, 2), and appeared confirmed by the human MR (hMR) sequence determined by Arriza et al. (2), published as "Cloning of human mineralocorticoid receptor complementary DNA: structural and functional kinship with the glucocorticoid receptor." This kinship appears underscored by the data in Fig. 1Go, in which the percent amino acid identity between MR and the other three members of the subfamily [GR, progesterone receptor (PR), and androgen receptor (AR)] are compared for three species (human, rat, and mouse).


Figure 1
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  		Fig. 1. Homology between MR, GR, PR, and AR for Human, Rat, and Mouse Isoforms

Sequences were retrieved from the National Center for Biotechnology Information Entrez and aligned by using the AlignX function in the Vector NTI Suite 9 from Informax. The alignment is based on the Clustal W algorithm using default (Blosum 62mt2) matrix to detect similarities. We also performed analysis using various other matrices including Gonnet, Identity, BLOSUM series, and PAM series, and obtained similar results. FL, Full-length sequence.

 
As can be seen, in each of the three species, MR is closer to GR than to PR or AR in terms of the full-length sequence. The similarity of MR to GR in all species is significantly higher than to PR or AR (P < 0.05, Student’s paired t test), and there is no significant difference in similarities between MR to PR and MR to AR. On this basis, then, plus that of shared ligands, the assumption has been perhaps too easily made that MR and GR are closer to one another in evolutionary terms than to PR or AR, as shown in Fig. 2Go, the dendrogram proposed by the Nuclear Receptor Nomenclature Committee (3).


Figure 2
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  		Fig. 2. Dendrogram Representing the Members of the Nuclear Receptor Superfamily

Enlarged is the MR/GR/PR/AR subfamily. [Adapted from Cell 97:161–163, 1999 (3 ) with permission from Elsevier.]

 

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That this assumption may need to be rethought is suggested by the sequence data shown in Fig. 3Go. When hGR is taken as 100% (Fig. 3Go, top), on a full-length sequence basis, hMR is most distant, as it is for helices 3/4/5 and 3/4/5/12; only, and notably, is homology between GR and MR closest for the ligand binding domain (LBD). For PR, exactly the same relationship holds, with MR clearly the most distant on the basis of full-length sequence, helices 3/4/5, or helices 3/4/5/12: again, as for GR, the MR has closer homology in the LBD to PR than does PR with GR or AR. Finally, for AR (Fig. 3Go, bottom), the pattern is repeated: for the full-length sequence, helices 3/4/5 and helices 3/4/5/12, MR is clearly more distant from AR than are GR or PR. For the LBD, MR is intermediate in terms of homology: less than PR, more than GR. This pattern of homology is identical for rat and mouse, with minor differences in degree of separation, but exactly the same inference (P < 0.05, Student’s paired t test) able to be made (data not shown).


Figure 3
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  		Fig. 3. Homology between GR, PR, AR, and MR

Details are as for Fig. 1Go.

 
The interspecies differences within helices 3/4/5/12 are very low—three-residue variations in MR, two in GR, and none in PR or AR across human, mouse, and rat. The similarity between helices 3/4/5/12 of MR and GR, PR, or AR are 61 ± 2.3% (mean ± SD), 59 ± 1.2 and 59 ± 1.2%, respectively, with no difference between values by Student’s paired t test (P > 0.05), indicating that MR is equally distant from the other three receptors. When GR is taken as 100%, however, the similarity between GR and MR is significantly less than that between GR and PR or GR and AR. For PR and AR, exactly the same relationship holds, confirming MR as the most distant.

Our interpretation of these data is as follows. First, in terms of sequence, GR/PR/AR are closer to one another than any is to MR, which thus puts into question a common immediate ancestor for MR and GR. This separation is true for the full-length sequence, and for the cofactor binding helices in the LBD. For the LBD as a whole, however, a different picture emerges, where MR appear closer to GR than PR or AR are to GR, and closer to PR than GR or AR are to PR. In this context, it is perhaps noteworthy that, in addition to their equal, high affinity for aldosterone, cortisol, and corticosterone, MR have the same high affinity for progesterone, the physiological ligand for PR (4). In contrast, AR appear most different in terms of LBD homology (Figs. 2Go and 3Go, top, middle). Possible reasons underlying these similarities/differences are canvassed below.


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In a recent study from our laboratory (5), the MR LBD was shown to bind relatively few coactivator peptides when occupied by aldosterone or cortisol, with minor differences between ligands, and no cofactors (activator or repressor) in the presence of eplerenone. In the present study, we have directly compared the interaction of a panel of 39 cofactor binding peptides with LBD from MR, GR, PR, and AR. The mammalian two-hybrid assay was used to detect the interactions between each receptor LBD (as a VP16 fusion) and cofactor peptide (as a GAL4 fusion): detailed descriptions and sequences of these peptides are given in Ref. 5 . The fold interaction is the increase in reporter activity in the presence of excess cognate agonist ligand compared with vehicle: agonists used were as follows: MR, 10 nM aldosterone; GR, 1 µM cortisol; PR, 1 µM progesterone; AR, 100 nM dihydrotestosterone.

When the cofactor binding profiles are compared, two things can be immediately appreciated. First, the number of cofactors binding to MR LBD (Fig. 4AGo) is very much less than for GR (Fig. 4BGo) and PR (Fig. 4CGo) and not dissimilar to that for AR (Fig. 4DGo). Second, the extent of interactions is similarly much less for MR and AR than for GR/PR. In terms of cofactor binding, then, GR and PR would appear substantially closer to one another than to MR (or, indeed, to AR).


Figure 4
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  		Fig. 4. Cofactor Peptide Interactions with MR (A), GR (B), PR (C), and AR (D)

Mammalian two-hybrid assay was used in HEK-293 cells to detect the interactions between cofactor peptide (as Gal4 fusion) and VP16 fusion of steroid receptor LBDs (AR codons 652–919, GR codons 517–777, PK codons 659–933, and MR codons 686–984). The cofactor peptides used in this study are shown on the right; detailed description and sequences of these peptides are given in Ref. 5 .

 
As shown in Fig. 4Go, there is considerable commonality between MR and AR in terms of the restricted number and low levels of cofactor binding, but not in terms of particular peptides bound. There is, in fact, recent evidence that AR has evolved to interact with FXXLF rather than LXXLL peptides (6). In these studies, three residues (V713, V730, and M734) in the helix 3/4/5 region of AR have been shown critical for interactions with the FXXLF binding motif. Substituting one or more of these three residues for the corresponding amino acids in PR (L727V, I744V, and I748M in PR) allows PR to interact with the FXXLF motif, as is also the case for GR: MR does not appear to have been examined in parallel.

From comparative considerations, however, MR does appear to have followed a more divergent evolutionary path. As shown in Fig. 5Go, both lamprey PR and corticoid receptor have identical residues to hAR in two of three positions (V, I, M), suggesting that they are probably able to interact with a FXXLF motif. Other fish GR (rainbow trout, cichlid, flounder) and PR (eel) also have a conserved methionine (M734 equivalent), and, in some cases, a conserved valine (V713 equivalent). In contrast, all MR, from fish to human, have an invariant isoleucine rather than methionine at the M734 equivalent position. Estrogen receptors (ER) (and most other nuclear receptors) have isoleucine or valine, and none of them has methionine, at this position. These results are consistent with the possibility that lamprey PR and corticoid receptor may be able to interact weakly with the FXXLF motif; that other fish GR and PR progressively lose the ability to interact; and that AR has evolved to increase this ability. Fish MR, on the other hand, do not have the residues critical for this interaction, evidence for an early branching point between MR and AR—and further evidence that MR and GR do not derive from an immediate common ancestor.


Figure 5
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  		Fig. 5. Alignment of the Helix 3 to 5 Region of Fish Steroid Receptors

hAR and zebrafish RXR are included for comparison. The three residues in each receptor equivalent to the residues in hAR involved in FXXLF peptide interaction are underlined. The fish receptors are from the following species: Danio rerio (zebrafish), Oncorhynchus mykiss (rainbow trout), Platichthys flesus (flounder), Astatotilapia burtoni (cichlid), Anguilla japonica (eel), and Petromyzon marinus (lamprey).

 

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The final strand of evidence comes from the MR mutant sequence reported by Geller et al. (7) to be responsible for hypertension exacerbated by pregnancy. This point mutation results in a single amino acid change (S810L) in the hMR sequence; the mutant MR is constitutively partially activated, and binds progesterone and spironolactone—which are antagonists in wild-type MR—as agonists. The serine at 810 in hMR is conserved across species, in contrast with the invariant methionine at the corresponding position in GR/PR/AR, as shown in Fig. 6Go.


Figure 6
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  		Fig. 6. Alignment of the Helix 3 to 5 Region of Human MR/GR/PR/AR along with MR S810L Mutant, ER, and RXR

Underlined are the pairs of amino acids equivalent to MR A773 and S810 in each receptor.

 
As discussed by Geller et al., all of the other subfamily members (GR/PR/AR) have structures allowing the possibility of van der Waals interactions between the equivalent amino acids (glycine and methionine), as does the S810L mutant (alanine and leucine) but not the wild-type MR (alanine and serine). Similar interactions have been reported for both the ER and retinoid X receptor (RXR), which like the mutant MR have alanine and leucine at the equivalent positions in their sequences. Although these data do not prove that MR and GR do not share an immediate common ancestor, a parsimonious explanation would be that of a single L810S mutation (to the wild-type MR) from the primordial ancestral sequence shared with ER and RXR, conferring a degree of ligand selectivity and a full dynamic range of agonist/antagonist activity on a primordial C21 steroid receptor.


   DISCUSSION
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These sequence and cofactor binding data need to be considered in the context (and within the limits) of the endocrine physiology of mineralocorticoid, glucocorticoid, androgenic, and progestational hormones. If aldosterone is considered as the cognate ligand for MR, then all four receptors have affinity for their ligands appropriate for activation (or not), dependent on ambient free steroid levels. All four classes of steroids have different patterns of secretion: for cortisol and aldosterone, there is circadian variation in baseline levels, with cortisol rising in response to stress via the action of ACTH, and aldosterone selectively rising in response to Na+ deficiency/K+ loading via angiotensin II and plasma [K+]. Variation in plasma progesterone levels is menstrual in cycling women, with further elevations in plasma levels over luteal in response to chorionic gonadotropin in pregnancy. Androgen levels increase in the male at puberty and, after peaking over the following decade, progressively decline with age.

Glucocorticoids circulate at much higher levels, total and free, than aldosterone, testosterone, or progesterone in the nonpregnant woman; total progesterone levels in midpregnancy may be higher than nadir glucocorticoid levels, but progesterone is even more bound in plasma, to serum albumin, than is cortisol. Glucocorticoid levels are therefore appropriate, over the range of baseline/stress levels, to progressively increase GR occupancy and activation. There is now, however, considerable evidence that aldosterone is first found in terrestrial vertebrates, and not in fish (8, 9). On the other hand, a number of species of fish have been shown to express MR, much closer in sequence to mammalian MR than to fish GR, and for which the putative ligand is cortisol until proven otherwise. Once MR are considered as receptors for cortisol, in fish and in many mammalian nonepithelial cells (e.g. cardiomyocytes, most neurons) in which they are found, then physiological roles for an essentially always-occupied MR become a matter for speculation (10); other always-occupied receptors in the nuclear receptor family include hepatic nuclear factor 4 (11), retinoic-acid-related orphan receptor (12), and nuclear receptor E75 (13). We therefore propose the following hypotheses.


   HYPOTHESES
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1) That the sequence data highlighted by Geller et al. are consistent with a direct descent of MR from the primordial ancestral receptor also giving rise to RXR and ER, with the crucial mutation of L810S in the ancestral sequence converting it from a constitutively partially active species, and one fully activated by both cortisol and progesterone, to one which appears inactive when unoccupied, sees progesterone as antagonist, and glucocorticoids as agonist or antagonist depending on the circumstances (10).

2) That over the course of evolution particular ligands may "shape" the LBD, by constraining inactivating mutations, and allowing mutations that do not interfere with or favor selectivity. This is consistent with the AR LBD, for which the physiological ligands are the C19 steroids dihydrotestosterone and testosterone, being the furthest removed from the other three subfamily members, which are C21 steroid specific. Similarly consistent with such a hypothesis is that both GR and PR are more different in their LBD than either is from MR, not surprising in that MR binds corticosterone, deoxycorticosterone, cortisol, aldosterone, and progesterone (1, 2, 4) with equivalent, high affinity. PR are selective for progestins, and GR for physiological glucocorticoids over aldosterone and androgens, although they too show reasonable affinity for progesterone (14). The maintained high affinity of MR for progesterone is compatible with a hitherto poorly explored role for this steroid as (probably) an obligate MR antagonist, for which there is some suggestion from studies in the placenta (15, 16).

3) That over the course of evolution the receptor "ground state," i.e. unoccupied at nadir ligand concentrations (AR, PR, GR) or essentially always occupied (by glucocorticoids: MR; Ref. 17), may shape the cofactor binding profile for LXXLL or FXXLF binding peptides and thus the extent of activation. Consistent with this possibility are the differences in helix 3/4/5/12 between MR and the other three subfamily members, and the differences in cofactor binding and extent of activation.

4) That terrestrial animals, faced with electrolyte homeostasis in a nonaqueous environment, produce relatively low levels of aldosterone either by a dedicated aldosterone synthase (e.g. man, rat) or via the zone-specific activity of a common 11ß-hydroxylase (e.g. bovine) in response to Na+ deficiency or K+ load. Aldosterone is an obligate MR agonist, and its secretion at low levels compared with glucocorticoids may reflect the damage MR activation can cause when it affects even a small percentage of nonepithelial MR normally unprotected by the cortisol-debulking, reduced nicotinamide adenine dinucleotide-generating enzyme 11ß-hydroxysteroid dehydrogenase type 2 (18); and finally

5) That given the extent of homology between the MR/GR/PR/AR subfamily members in terms of full-length sequence, and the clear differences between MR and the others (helix 3/4/5/12), and between AR and the others (LBD as a whole), a revised dendrogram might look as shown on the right of Fig. 7Go—with MR branching as a distinct family member, and GR and PR sharing a common immediate evolutionary ancestor. An argument might be made that AR rather than MR is the first to branch off, on sequence homology grounds; we have chosen to place MR as the first branch, on the basis of the sequence data shown in Fig. 6Go.


Figure 7
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  		Fig. 7. Proposed Model of the Phylogenetic Relationship of the MR/GR/PR/AR Subfamily

In the conventional dendrogram (left), MR and GR evolve from a common immediate ancestor. In the proposed new dendrogram (right), MR branches before the divergence of the other three members.

 

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Any model of evolutionary relationships between proteins, even in an obviously closely related family such as that shown in Fig. 7Go, is essentially probabilistic. The crystalline structure of the MR LBD has been reported recently for the S810L mutant hMR (19, 20) and a mutant MR (C808S) with wild-type activity (20, 21). In essence, maximal wild-type MR activation requires hydrogen bonding networks that stabilize interactions between helix 3 and the loop preceding helix 12, and between ligand and helix 10. The residues involved in the hydrogen bonding networks are identical in AR/GR/MR/PR, so that they are unlikely to contribute to the differential cofactor interactions. The MR S810L mutant structures also reveal that the hydrophobic interaction between helix 3 and helix 5 involving L810 can partially offset the requirement of hydrogen bonding to stabilize the active receptor conformation. As discussed earlier, this hydrophobic interaction is conserved in AR/GR/PR but not in wild-type MR. MR crystal structures thus clearly provide supporting evidence that MR activation is different from that of GR.

The LBDs of MR/GR/PR/AR subfamily are encoded by five exons, with helices 3/4/5 encoded by two exons and helices 11/12 by another; the rest of the LBD is encoded by the remaining two exons, with an intron between helix 8 and helix 9, and the length of each exon and the exon-intron boundaries highly conserved. Examination of the sequence homology of this region indicates that, in helices 6/7/8, MR is also more distant from GR than GR is from PR or AR. In the exon encoding helices 9/10, MR is overwhelmingly closer to GR (similarity, 68%) than to PR or AR is to GR (53 or 55%, respectively), so that this exon appears to underlie the similarity of LBD sequences as a whole between MR and GR. It has been noted that the helix 9/10 region of steroid receptors abruptly loses homology from other nuclear receptors (22), suggesting that exon shuffling contributes significantly to the evolution of this region.

On the other hand, the current assignation of a close relationship between MR and GR appears to be predominantly (and perhaps subconsciously) driven by their commonality in terms of corticosteroid ligands. As noted previously, however, MR appear unique within the subfamily in that they are essentially always occupied by cortisol in nonepithelial tissues, normally in tonic inhibitory mode, and with cortisol·MR complexes inactivated in epithelia by the action of 11ß-hydroxysteroid dehydrogenase type 2 to allow selectivity of aldosterone action. Because aldosterone is found only in terrestrial vertebrates, cortisol is thus the original evolutionary driver for MR. The present studies show a clear distinction in LXXLL cofactor binding between GR and PR, on the one hand, and MR and AR on the other. The very low level of LXXLL interactions with MR LBD shown previously (5), and the much weaker MR FXXLF binding, given the evolutionary (Fig. 5Go) and the GR/PR mutation data (6), are consistent with a unique evolutionary driver for an always-occupied MR—and with a much closer relationship between GR and PR.


   ACKNOWLEDGMENTS
 
We thank Peter Fuller for his constructive reading of this manuscript in draft, and Nataliia Krasnoperova, Monica Hultman, and Sarah Du for technical assistance.


   FOOTNOTES
 
First Published Online September 29, 2005

Abbreviations: AR, Androgen receptor; ER, estrogen receptor; GR, glucocorticoid receptor; h, human; LBD, ligand binding domain; MR, mineralocorticoid receptor; PR, progesterone receptor.

Received for publication June 23, 2005. Accepted for publication September 15, 2005.


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NURSA Molecule Pages Link:

Nuclear Receptors:   RXRα  |  GR  |  MR  |  PR  |  AR
Coregulators:   RIP140  |  NSD1  |  TRAP220  |  PGC-1  |  TIF1α  |  LCoR  |  PRIC285  |  NIX1  |  CBP  |  p300  |  Tip60  |  SRC-1  |  GRIP1  |  AIB1  |  ARA70  |  CIA  |  ASC-2  |  ERAP140
Ligands:   Hydrocortisone  |  Dihydrotestosterone  |  Aldosterone  |  Progesterone



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Molecular Cloning, Characterization, and Evolutionary Analysis of Estrogen Receptors from Phylogenetically Ancient Fish
Endocrinology, December 1, 2008; 149(12): 6300 - 6310.
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B. Cloke, K. Huhtinen, L. Fusi, T. Kajihara, M. Yliheikkila, K.-K. Ho, G. Teklenburg, S. Lavery, M. C. Jones, G. Trew, et al.
The Androgen and Progesterone Receptors Regulate Distinct Gene Networks and Cellular Functions in Decidualizing Endometrium
Endocrinology, September 1, 2008; 149(9): 4462 - 4474.
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J. M. C. Connell, S. M. MacKenzie, E. M. Freel, R. Fraser, and E. Davies
A Lifetime of Aldosterone Excess: Long-Term Consequences of Altered Regulation of Aldosterone Production for Cardiovascular Function
Endocr. Rev., April 1, 2008; 29(2): 133 - 154.
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M. Agler, M. Prack, Yingjie Zhu, J. Kolb, K. Nowak, R. Ryseck, Ding Shen, M. E. Cvijic, J. Somerville, S. Nadler, et al.
A High-Content Glucocorticoid Receptor Translocation Assay for Compound Mechanism-of-Action Evaluation
J Biomol Screen, December 1, 2007; 12(8): 1029 - 1041.
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M. Caprio, B. Feve, A. Claes, S. Viengchareun, M. Lombes, and M.-C. Zennaro
Pivotal role of the mineralocorticoid receptor in corticosteroid-induced adipogenesis
FASEB J, July 1, 2007; 21(9): 2185 - 2194.
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B. Pitt and G. S. Pitt
Added Benefit of Mineralocorticoid Receptor Blockade in the Primary Prevention of Sudden Cardiac Death
Circulation, June 12, 2007; 115(23): 2976 - 2982.
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J. W. Funder
Aldosterone and the Cardiovascular System: Genomic and Nongenomic Effects
Endocrinology, December 1, 2006; 147(12): 5564 - 5567.
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