Progesterone: An Enigmatic Ligand for the Mineralocorticoid Receptor

Physiological Role ◽

Reproductive Physiology ◽

Elephant Shark ◽

Terrestrial Vertebrates ◽

High Affinity ◽

Reproductive Tissues ◽

Terrestrial Vertebrate ◽

Functional Consequences ◽

Cartilaginous Fishes

The progesterone receptor (PR) mediates progesterone regulation of female reproductive physiology, as well as gene transcription in non-reproductive tissues, such as brain, bone, lung and vasculature, in both women and men. An unusual property of progesterone is its high affinity for the mineralocorticoid receptor (MR), which regulates electrolyte transport in the kidney in humans and other terrestrial vertebrates. In humans, rats, alligators and frogs, progesterone antagonizes activation of the MR by aldosterone, the physiological mineralocorticoid in terrestrial vertebrates. In contrast, in elephant shark, ray-finned fishes and chickens, progesterone activates the MR. Interestingly, cartilaginous fishes and ray-finned fishes do not synthesize aldosterone, raising the question of which steroid(s) activate the MR in cartilaginous fishes and ray-finned fishes. The simpler synthesis of progesterone, compared to cortisol and other corticosteroids, makes progesterone a candidate physiological activator of the MR in elephant sharks and ray-finned fishes. Elephant shark and ray-finned fish MRs are expressed in diverse tissues, including heart, brain and lung, as well as, ovary and testis, two reproductive tissues that are targets for progesterone, which together suggests a multi-faceted physiological role for progesterone activation of the MR in elephant shark and ray-finned fish. The functional consequences of progesterone as an antagonist of some terrestrial vertebrate MRs and as an agonist of fish and chicken MRs are not fully understood. Indeed, little is known of physiological activities of progesterone via any vertebrate MR.

Transcriptional Activation of Elephant Shark Mineralocorticoid Receptor by Corticosteroids, Progesterone and Spironolactone

10.20944/preprints201903.0001.v1 ◽

2019 ◽

Author(s):

Yoshinao Katsu ◽

Satomi Kohno ◽

Kaori Oka ◽

Xiaozhi Lin ◽

Sumika Otake ◽

...

Keyword(s):

Sequence Analysis ◽

Human Brain ◽

Cartilaginous Fish ◽

Full Length ◽

Rna Sequence ◽

Elephant Shark ◽

Terrestrial Vertebrates ◽

Cartilaginous Fishes

We report the analysis of activation by corticosteroids and progesterone of full-length mineralocorticoid receptor (MR) from elephant shark, a cartilaginous fish belonging to the oldest group of jawed vertebrates.  Based on their measured activities, aldosterone, cortisol, 11-deoxycorticosterone, corticosterone, 11-deoxcortisol, progesterone and 19-norprogesterone are potential physiological mineralocorticoids.  However, aldosterone, the physiological mineralocorticoid in humans and other terrestrial vertebrates, is not found in cartilaginous or ray-finned fishes.  Because progesterone is a precursor for corticosteroids that activate elephant shark MR, we propose that progesterone was an ancestral ligand for elephant shark MR.  Although progesterone activates ray-finned fish MRs, progesterone does not activate human, amphibian or alligator MRs, suggesting that during the transition to terrestrial vertebrates, progesterone lost the ability to activate the MR.  Comparison of RNA-sequence analysis of elephant shark MR with that of human MR suggests that MR expression in the human brain, heart, ovary, testis and other non-epithelial tissues evolved in cartilaginous fishes.  Together, these data suggest that progesterone-activated MR may have unappreciated functions in elephant shark ovary and testis.

Transcriptional Activation of Elephant Shark Mineralocorticoid Receptor by Corticosteroids, Progesterone and Spironolactone

10.32942/osf.io/u56ar ◽

2019 ◽

Cited By ~ 1

Author(s):

Yoshinao Katsu ◽

Satomi Kohno ◽

Kaori Oka ◽

Xiaozhi Lin ◽

Sumika Otake ◽

...

Keyword(s):

Sequence Analysis ◽

Human Brain ◽

Cartilaginous Fish ◽

Full Length ◽

Rna Sequence ◽

Elephant Shark ◽

Terrestrial Vertebrates ◽

Cartilaginous Fishes

We report the analysis of activation by corticosteroids and progesterone of full-length mineralocorticoid receptor (MR) from elephant shark, a cartilaginous fish belonging to the oldest group of jawed vertebrates. Based on their measured activities, aldosterone, cortisol, 11-deoxycorticosterone, corticosterone, 11-deoxcortisol, progesterone and 19-norprogesterone are potential physiological mineralocorticoids. However, aldosterone, the physiological mineralocorticoid in humans and other terrestrial vertebrates, is not found in cartilaginous or ray-finned fishes. Because progesterone is a precursor for corticosteroids that activate elephant shark MR, we propose that progesterone was an ancestral ligand for elephant shark MR. Although progesterone activates ray-finned fish MRs, progesterone does not activate human, amphibian or alligator MRs, suggesting that during the transition to terrestrial vertebrates, progesterone lost the ability to activate the MR. Comparison of RNA-sequence analysis of elephant shark MR with that of human MR suggests that MR expression in the human brain, heart, ovary, testis and other non-epithelial tissues evolved in cartilaginous fishes. Together, these data suggest that progesterone-activated MR may have unappreciated functions in elephant shark ovary and testis.

Transcriptional activation of elephant shark mineralocorticoid receptor by corticosteroids, progesterone, and spironolactone

Science Signaling ◽

10.1126/scisignal.aar2668 ◽

2019 ◽

Vol 12 (584) ◽

pp. eaar2668 ◽

Cited By ~ 8

Author(s):

Yoshinao Katsu ◽

Satomi Kohno ◽

Kaori Oka ◽

Xiaozhi Lin ◽

Sumika Otake ◽

...

Keyword(s):

Transcription Factors ◽

Common Ancestor ◽

Cartilaginous Fish ◽

Reproductive Physiology ◽

Elephant Shark ◽

Terrestrial Vertebrates ◽

The Common ◽

The Brain

The mineralocorticoid receptor (MR) is a nuclear receptor and part of a large and diverse family of transcription factors that also includes receptors for glucocorticoids, progesterone, androgens, and estrogens. The corticosteroid aldosterone is the physiological activator of the MR in humans and other terrestrial vertebrates; however, its activator is not known in cartilaginous fish, the oldest group of extant jawed vertebrates. Here, we analyzed the ability of corticosteroids and progesterone to activate the full-length MR from the elephant shark (Callorhinchus milii). On the basis of their measured activities, aldosterone, cortisol, 11-deoxycorticosterone, corticosterone, 11-deoxcortisol, progesterone, and 19-norprogesterone are potential physiological mineralocorticoids. However, aldosterone, the physiological mineralocorticoid in humans and other terrestrial vertebrates, is not found in cartilaginous or ray-finned fish. Although progesterone activates MRs in ray-finned fish, progesterone does not activate MRs in humans, amphibians, or alligator, suggesting that during the transition to terrestrial vertebrates, progesterone lost the ability to activate the MR. Both elephant shark MR and human MR are expressed in the brain, heart, ovary, testis, and other nonepithelial tissues, suggesting that MR expression in diverse tissues evolved in the common ancestor of jawed vertebrates. Our data suggest that 19-norprogesterone– and progesterone-activated MR may have unappreciated functions in reproductive physiology.

Molecular evolution of the switch for progesterone and spironolactone from mineralocorticoid receptor agonist to antagonist

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1903172116 ◽

2019 ◽

Vol 116 (37) ◽

pp. 18578-18583 ◽

Cited By ~ 7

Author(s):

Peter J. Fuller ◽

Yi-Zhou Yao ◽

Ruitao Jin ◽

Sitong He ◽

Beatriz Martín-Fernández ◽

...

Keyword(s):

Ligand Binding ◽

Conformational Changes ◽

Steroid Receptors ◽

Binding Domain ◽

Ligand Binding Domain ◽

Site Directed Mutagenesis ◽

Structural Basis ◽

Terrestrial Vertebrates ◽

Terrestrial Vertebrate

The mineralocorticoid receptor (MR) is highly conserved across vertebrate evolution. In terrestrial vertebrates, the MR mediates sodium homeostasis by aldosterone and also acts as a receptor for cortisol. Although the MR is present in fish, they lack aldosterone. The MR binds progesterone and spironolactone as antagonists in human MR but as agonists in zebrafish MR. We have defined the molecular basis of these divergent responses using MR chimeras between the zebrafish and human MR coupled with reciprocal site-directed mutagenesis and molecular dynamic (MD) simulation based on the crystal structures of the MR ligand-binding domain. Substitution of a leucine by threonine in helix 8 of the ligand-binding domain of the zebrafish MR confers the antagonist response. This leucine is conserved across fish species, whereas threonine (serine in rodents) is conserved in terrestrial vertebrate MR. MD identified an interaction of the leucine in helix 8 with a highly conserved leucine in helix 1 that stabilizes the agonist conformation including the interaction between helices 3 and 5, an interaction which has previously been characterized. This switch in the MR coincides with the evolution of terrestrial vertebrates and of aldosterone synthesis. It was perhaps mandatory if the appearance of aldosterone as a specific mediator of the homeostatic salt retention was to be tolerated. The conformational changes also provide insights into the structural basis of agonism versus antagonism in steroid receptors with potential implications for drug design in this important therapeutic target.

Transcriptional Activation of Elephant Shark Mineralocorticoid Receptor by Corticosteroids, Progesterone and Spironolactone

10.1101/265348 ◽

2018 ◽

Author(s):

Yoshinao Katsu ◽

Satomi Kohno ◽

Kaori Oka ◽

Xiaozhi Lin ◽

Sumika Otake ◽

...

Keyword(s):

Common Ancestor ◽

Cartilaginous Fish ◽

Full Length ◽

Elephant Shark ◽

Terrestrial Vertebrates ◽

Epithelial Tissues ◽

The Common ◽

The Brain

AbstractWe report the analysis of activation of full-length mineralocorticoid receptor (MR) from elephant shark, a cartilaginous fish belonging to the oldest group of jawed vertebrates by corticosteroids and progesterone. Based on their measured activities, aldosterone, cortisol, 11-deoxycorticosterone, corticosterone, 11-deoxcortisol, progesterone and 19-norprogesterone are potential physiological mineralocorticoids. However, aldosterone, the physiological mineralocorticoid in humans and other terrestrial vertebrates, is not found in cartilaginous or ray-finned fishes. Although progesterone activates ray-finned fish MRs, progesterone does not activate human, amphibian or alligator MRs, suggesting that during the transition to terrestrial vertebrates, progesterone lost the ability to activate the MR. Both elephant shark MR and human MR are expressed in the brain, heart, ovary, testis and other non-epithelial tissues, indicating that MR expression in diverse tissues evolved in the common ancestor of jawed vertebrates. Our data suggest that progesterone-activated MR may have unappreciated functions in elephant shark ovary and testis.

N-terminal Domain Regulates Steroid Activation of Elephant Shark Glucocorticoid and Mineralocorticoid Receptors

10.1101/822718 ◽

2019 ◽

Author(s):

Yoshinao Katsu ◽

Islam MD Shariful ◽

Xiaozhi Lin ◽

Wataru Takagi ◽

Hiroshi Urushitani ◽

...

Keyword(s):

Glucocorticoid Receptor ◽

Functional Divergence ◽

Full Length ◽

Mineralocorticoid Receptors ◽

Elephant Shark ◽

Terminal Domain ◽

Cartilaginous Fishes ◽

Steroid Binding

AbstractOrthologs of human glucocorticoid receptor (GR) and human mineralocorticoid receptor (MR) first appear in cartilaginous fishes. Subsequently, the MR and GR diverged to respond to different steroids: the MR to aldosterone and the GR to cortisol and corticosterone. We report that cortisol, corticosterone and aldosterone activate full-length elephant shark GR, and progesterone, which activates elephant shark MR, does not activate elephant shark GR. However, progesterone inhibits steroid binding to elephant shark GR, but not to human GR. Together, this indicates partial functional divergence of elephant shark GR from the MR. Deletion of the N-terminal domain (NTD) from elephant shark GR (truncated GR) reduced the response to corticosteroids, while truncated and full-length elephant shark MR had similar responses to corticosteroids. Swapping of NTDs of elephant shark GR and MR yielded an elephant shark MR chimera with full-length GR-like increased activation by corticosteroids and progesterone compared to full-length elephant shark MR. Elephant shark MR NTD fused to GR DBD+LBD had similar activation as full-length MR, indicating that the MR NTD lacked GR-like NTD activity. We propose that NTD activation of human GR evolved early in GR divergence from the MR.

Aldosterone, Dexamethasone and Triamcinolone Activate African Lungfish Mineralocorticoid Receptor: Increased Activation After Removal of the Amino-Terminal Domain

10.1101/2021.05.28.446239 ◽

2021 ◽

Author(s):

Yoshinao Katsu ◽

Shin Oana ◽

Xiaozhi Lin ◽

Susumu Hyodo ◽

Michael E. Baker

Keyword(s):

Activation Function ◽

Binding Domain ◽

Full Length ◽

Terrestrial Vertebrates ◽

Amino Terminal ◽

Terminal Domain ◽

Cartilaginous Fishes ◽

African Lungfish

A distinct mineralocorticoid receptor (MR) ortholog first appears in cartilaginous fishes, such as sharks, skates, rays and chimaeras. Although aldosterone, the main physiological mineralocorticoid in humans and other terrestrial vertebrates, is a transcriptional activator of skate MR and elephant shark MR, aldosterone is not synthesized by cartilaginous fishes. Aldosterone, first appears in lungfish, which are lobe-finned fish that are forerunners of terrestrial vertebrates. Aldosterone activation of the MR regulates internal homeostasis of water, sodium and potassium, which was critical in the conquest of land by vertebrates. We studied transcriptional activation of the slender African lungfish (Protopterus dolloi) MR by aldosterone, other corticosteroids and progesterone and find that aldosterone, 11-deoxycorticosterone, 11-deoxycortisol and progesterone have half-maximal responses (EC50s) below 1 nM and are potential physiological mineralocorticoids. In contrast, EC50s for corticosterone and cortisol were 23 nM and 66 nM, respectively. Unexpectedly, truncated lungfish MR, consisting of the DNA-binding domain, hinge domain and steroid-binding domain, had a stronger response to aldosterone, other corticosteroids and progesterone than did full-length lungfish MR, indicating that an allosteric action of the N-terminal domain represses steroid activation of lungfish MR. This contrasts to human MR in which the N-terminal domain contains an activation function. BLAST searches of GenBank did not retrieve a GR ortholog, leading us to test dexamethasone and triamcinolone for activation of lungfish MR. At 10 nM, both synthetic glucocorticoids are about 4-fold stronger than 10 nM aldosterone in activating full-length lungfish MR, leading us to propose that lungfish MR also functions as a GR.

Divergent Evolution of Progesterone and Mineralocorticoid Receptors in Terrestrial Vertebrates and Fish Influences Endocrine Disruption

10.20944/preprints202111.0396.v1 ◽

2021 ◽

Author(s):

Michael Baker

Keyword(s):

Binding Sites ◽

Endocrine Disrupting Chemicals ◽

Divergent Evolution ◽

Industrial Chemicals ◽

Elephant Shark ◽

Terrestrial Vertebrates ◽

Terrestrial Vertebrate ◽

Endocrine Disrupting ◽

Development And Differentiation ◽

Potent Agonist

There is much concern about disruption of endocrine physiology regulated by steroid hormones in humans, other terrestrial vertebrates and fish by industrial chemicals, such as bisphenol A, and pesticides, such as DDT. These endocrine-disrupting chemicals influence steroid-mediated physiology in humans and other vertebrates by competing with steroids for receptor binding sites, disrupting diverse responses involved in reproduction, development and differentiation. Here I discuss that due to evolution of the progesterone receptor (PR) and mineralocorticoid receptor (MR) after ray-finned fish and terrestrial vertebrates diverged from a common ancestor, each receptor evolved to respond to different steroids in ray-finned fish and terrestrial vertebrates. In elephant shark, a cartilaginous fish, ancestral to ray-finned fish and terrestrial vertebrates, both progesterone and 17,20-beta-dihydroxy-progesterone activate the PR. During the evolution of ray-finned fish and terrestrial vertebrates, the PR in terrestrial vertebrates continued responding to progesterone and evolved to weakly respond to 17,20-beta-dihydroxy-progesterone. In contrast, the physiological progestin for the PR in zebrafish and other ray-finned fish is 17,20-beta-dihydroxy-progesterone, and ray-finned fish PR responds weakly to progesterone. The MR in fish and terrestrial vertebrates also diverged to have different responses to progesterone. Progesterone is a potent agonist for elephant shark MR, zebrafish MR and other fish MRs, in contrast to progesterone’s opposite activity as an antagonist for aldosterone, the physiological mineralocorticoid for human MR. These different physiological ligands for fish and terrestrial vertebrate PR and MR need to be considered in applying data for their disruption by chemicals in fish and terrestrial vertebrates to each other.

Evolution of the Mineralocorticoid Receptor: Sequence, Structure and Function

10.1101/098921 ◽

2017 ◽

Author(s):

Michael E. Baker ◽

Yoshinao Katsu

Keyword(s):

Sequence Structure ◽

Strong Response ◽

Terrestrial Vertebrates ◽

Cartilaginous Fishes ◽

And Function ◽

Corticoid Receptor ◽

Jawless Fish ◽

Combine Sequence

Abstract.The mineralocorticoid receptor (MR) is descended from a corticoid receptor (CR), which has descendants in lamprey and hagfish, cyclostomes (jawless fish), a taxon that evolved at the base of the vertebrate line. A distinct MR and GR first appear in cartilaginous fishes (Chondrichthyes), such as sharks, skates, rays and chimaeras. Skate MR has a strong response to corticosteroids that are mineralocorticoids and glucocorticoids in humans. The half-maximal responses (EC50s) for skate MR for the mineralocorticoids aldosterone and 11-deoxycorticosterone are 0.07 nM and 0.03 nM, respectively. EC50s for the glucocorticoids cortisol and corticosterone are 1 nM and 0.09 nM, respectively. The physiological mineralocorticoid in ray-finned fish, which do not synthesize aldosterone, is not fully understood because several 3-ketosteroids, including cortisol, 11-deoxycortisol, corticosterone, 11-deoxycorticosterone and progesterone are transcriptional activators of fish MR. Divergence of the MR and GR in terrestrial vertebrates, which synthesize aldosterone, led to increased selectivity of the MR for aldosterone, coupled with a diminished response to cortisol and corticosterone. Here, we combine sequence analysis of the CR and vertebrate MRs and GRs, analysis of crystal structures of human MR and GR and data on transcriptional activation by 3-ketosteroids of wild-type and mutant MRs and GRs to investigate the evolution of selectivity for 3-ketosteroids by the MR in terrestrial vertebrates and ray-finned fish, as well as the basis for binding of some glucocorticoids by human MR and other vertebrate MRs.

N-terminal Domain Regulates Steroid Activation of Elephant Shark Glucocorticoid and Mineralocorticoid Receptors

10.21203/rs.3.rs-93334/v1 ◽

2020 ◽

Author(s):

Yoshinao Katsu ◽

Islam MD Shari ◽

Xiaozhi Lin ◽

Wataru Takagi ◽

Hiroshi Urushitani ◽

...

Keyword(s):

Glucocorticoid Receptor ◽

Functional Divergence ◽

Full Length ◽

Mineralocorticoid Receptors ◽

Elephant Shark ◽

Terminal Domain ◽

Cartilaginous Fishes ◽

Steroid Binding

Abstract Orthologs of human glucocorticoid receptor (GR) and human mineralocorticoid receptor (MR) first appear in cartilaginous fishes. Subsequently, the MR and GR diverged to respond to different steroids: the MR to aldosterone and the GR to cortisol and corticosterone. We report that cortisol, corticosterone and aldosterone activate full-length elephant shark GR, and progesterone, which activates elephant shark MR, does not activate elephant shark GR. However, progesterone inhibits steroid binding to elephant shark GR, but not to human GR. Together, this indicates partial functional divergence of elephant shark GR from the MR. Deletion of the N-terminal domain (NTD) from elephant shark GR (truncated GR) reduced the response to corticosteroids, while truncated and full-length elephant shark MR had similar responses to corticosteroids. Swapping of NTDs of elephant shark GR and MR yielded an elephant shark MR chimera with full-length GR-like increased activation by corticosteroids and progesterone compared to full-length elephant shark MR. Elephant shark MR NTD fused to GR DBD+LBD had similar activation as full-length MR, indicating that the MR NTD lacked GR-like NTD activity. We propose that NTD activation of human GR evolved early in GR divergence from the MR.