This Article Full Text Full Text (PDF) All Versions of this Article: 20/7/1471    most recent Author Manuscript (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager NURSA Molecule Pages Link Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hu, X. Articles by Funder, J. W. Search for Related Content PubMed PubMed Citation Articles by Hu, X. Articles by Funder, J. W.

The Evolution of Mineralocorticoid Receptors

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.

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.

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

This article has been cited by other articles:

				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. [Abstract] [Full Text] [PDF]

				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. [Abstract] [Full Text] [PDF]

				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. [Abstract] [PDF]

				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. [Abstract] [Full Text] [PDF]

				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. [Full Text] [PDF]

				J. W. Funder Aldosterone and the Cardiovascular System: Genomic and Nongenomic Effects Endocrinology, December 1, 2006; 147(12): 5564 - 5567. [Abstract] [Full Text] [PDF]