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

2019 ◽  
Author(s):  
Yoshinao Katsu ◽  
Islam MD Shariful ◽  
Xiaozhi Lin ◽  
Wataru Takagi ◽  
Hiroshi Urushitani ◽  
...  
Keyword(s):  
Glucocorticoid Receptor ◽  
Mineralocorticoid 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.

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

2020 ◽  
Author(s):  
Yoshinao Katsu ◽  
Islam MD Shari ◽  
Xiaozhi Lin ◽  
Wataru Takagi ◽  
Hiroshi Urushitani ◽  
...  
Keyword(s):  
Glucocorticoid Receptor ◽  
Mineralocorticoid 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.

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

2019 ◽  
Author(s):  
Yoshinao Katsu ◽  
Satomi Kohno ◽  
Kaori Oka ◽  
Xiaozhi Lin ◽  
Sumika Otake ◽  
...  
Keyword(s):  
Sequence Analysis ◽  
Human Brain ◽  
Transcriptional Activation ◽  
Mineralocorticoid Receptor ◽  
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.

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

2019 ◽  
Author(s):  
Yoshinao Katsu ◽  
Satomi Kohno ◽  
Kaori Oka ◽  
Xiaozhi Lin ◽  
Sumika Otake ◽  
...  
Keyword(s):  
Sequence Analysis ◽  
Human Brain ◽  
Transcriptional Activation ◽  
Mineralocorticoid Receptor ◽  
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.

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

2021 ◽  
Author(s):  
Yoshinao Katsu ◽  
Shin Oana ◽  
Xiaozhi Lin ◽  
Susumu Hyodo ◽  
Michael E. Baker
Keyword(s):  
Transcriptional Activation ◽  
Mineralocorticoid Receptor ◽  
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.

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

2021 ◽  
Author(s):  
Yoshinao Katsu ◽  
Shin Oana ◽  
Xiaozhi Lin ◽  
Susumu Hyodo ◽  
Michael E. Baker
Keyword(s):  
Transcriptional Activation ◽  
Mineralocorticoid Receptor ◽  
Activation Function ◽  
Binding Domain ◽  
Full Length ◽  
Terrestrial Vertebrates ◽  
Amino Terminal ◽  
Terminal Domain ◽  
Cartilaginous Fishes ◽  
African Lungfish

Abstract 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.

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

2021 ◽  
pp. 105845
Author(s):  
Yoshinao Katsu ◽  
Islam M.D. Shariful ◽  
Xiaozhi Lin ◽  
Wataru Takagi ◽  
Hiroshi Urushitani ◽  
...  
Keyword(s):  
Mineralocorticoid Receptors ◽  
Elephant Shark ◽  
Terminal Domain

scholarly journals Progesterone: An Enigmatic Ligand for the Mineralocorticoid Receptor

2020 ◽  
Author(s):  
Michael Baker ◽  
Yoshinao Katsu
Keyword(s):  
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.

scholarly journals Evolution of human, chicken, alligator, frog and zebrafish mineralocorticoid receptors: Allosteric influence on steroid specificity

2017 ◽  
Author(s):  
Yoshinao Katsu ◽  
Kaori Oka ◽  
Michael E. Baker
Keyword(s):  
Dna Binding ◽  
Ligand Binding ◽  
Binding Domain ◽  
Ligand Binding Domain ◽  
Full Length ◽  
Dna Binding Domain ◽  
Mineralocorticoid Receptors ◽  
Terminal Domain ◽  
Terrestrial Vertebrate ◽  
Hinge Domain

AbstractWe studied the response to aldosterone, 11-deoxycorticosterone, 11-deoxycortisol, cortisol, corticosterone, progesterone, 19-norprogesterone and spironolactone of human, chicken, alligator, frog and zebrafish full-length mineralocorticoid receptors (MRs) and truncated MRs, lacking the N-terminal domain (NTD) and DNA-binding domain (DBD), in which the hinge domain and ligand binding domain (LBD) were fused to a GAL4-DBD. Compared to full-length MRs, some vertebrate MRs required higher steroid concentrations to activate GAL4-DBD-MR-hinge/LBD constructs. For example, 11-deoxycortisol activated all full-length vertebrate MRs, but did not activate truncated terrestrial vertebrate MRs and was an agonist for truncated zebrafish MR. Progesterone, 19-norProgesterone and spironolactone did not activate full-length and truncated human, alligator and frog MRs. However, at 10 nM, these steroids activated full-length chicken and zebrafish MRs; at 100 nM, these steroids had little activity for truncated chicken MRs, while retaining activity for truncated zebrafish MRs, evidence that regulation of progestin activation of chicken MR resides in NTD/DBD and of zebrafish MR in hinge-LBD. Zebrafish and chicken MRs contain a serine corresponding to Ser810 in human MR, required for its antagonism by progesterone, suggesting novel regulation of progestin activation of chicken and zebrafish MRs. Progesterone may be a physiological activator of chicken and zebrafish MRs.

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

2018 ◽  
Author(s):  
Yoshinao Katsu ◽  
Satomi Kohno ◽  
Kaori Oka ◽  
Xiaozhi Lin ◽  
Sumika Otake ◽  
...  
Keyword(s):  
Transcriptional Activation ◽  
Mineralocorticoid Receptor ◽  
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.

Sign in / Sign up

Export Citation Format

Share Document