Biology subjects

Baker, M. E.

Publications and source records attributed to Baker, M. E..

4 recordsLinked to original sources

bioRxiv2018

Transcriptional Activation of a Cartilaginous Fish (Elephant Shark, Callorhinchus milii) Mineralocorticoid Receptor by Corticosteroids, Progestins and Spironolactone

We 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.

physiology↗

bioRxiv2017

The promiscuous estrogen receptor: evolution of physiological estrogens and response to phytochemicals and endocrine disruptors

Many actions of estradiol (E2), the principal physiological estrogen in vertebrates, are mediated by estrogen receptor- (ER) and ER{beta}. An important physiological feature of vertebrate ERs is their promiscuous response to several physiological steroids, including estradiol (E2), {Delta}5-androstenediol, 5-androstanediol, and 27-hydroxycholesterol. A novel structural characteristic of {Delta}5-androstenediol, 5-androstanediol, and 27-hydroxycholesterol is the presence of a C19 methyl group, which precludes the presence of an aromatic A ring with a C3 phenolic group that is a defining property of E2. The structural diversity of these estrogens can explain the response of the ER to synthetic chemicals such as bisphenol A and DDT, which disrupt estrogen physiology in vertebrates, and the estrogenic activity of a variety of plant-derived chemicals such as genistein, coumestrol, and resveratrol. Diversity in the A ring of physiological estrogens also expands potential structures of industrial chemicals that can act as endocrine disruptors. Compared to E2, synthesis of 27-hydroxycholesterol and {Delta}5-androstenediol is simpler, leading us, based on parsimony, to propose that one or both of these steroids or a related metabolite was a physiological estrogen early in the evolution of the ER, with E2 assuming this role later as the canonical estrogen. In addition to the well-studied role of the ER in reproductive physiology, the ER also is an important transcription factor in non-reproductive tissues such as the cardiovascular system, kidney, bone, and brain. Some of these ER actions in non-reproductive tissues appeared early in vertebrate evolution, long before mammals evolved.

physiology↗

bioRxiv2017

Evolution of steroid specificity in human, chicken, alligator, frog and zebrafish mineralocorticoid receptors: Allosteric interactions affect steroid specificity

We 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.

physiology↗

bioRxiv2017

Evolution of the Mineralocorticoid Receptor: Sequence, Structure and Function

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.

physiology↗