HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 279, Issue 38, 39232-39239, September 17, 2004

This Article Full Text Full Text (PDF) All Versions of this Article: 279/38/39232    most recent M407436200v1 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 Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Marissal-Arvy, N. Articles by Mormède, P. Search for Related Content PubMed PubMed Citation Articles by Marissal-Arvy, N. Articles by Mormède, P. Social Bookmarking                      What's this?

Gain of Function Mutation in the Mineralocorticoid Receptor of the Brown Norway Rat^*

Nathalie Marissal-Arvy, Marc Lombès¶, Jessica Petterson, Marie-Pierre Moisan, and Pierre Mormède

From the Neurogénétique et Stress, Institut National de la Santé et de la Recherche Médicale, Unité 471, Institut National de la Recherche Agronomique Unité Mixte de Recherche 1243, and Université de Bordeaux 2, Institut François Magendie de Neurosciences, 1, rue Camille Saint Saëns, 33077 Bordeaux Cedex, France and the ^¶Institut National de la Santé et de la Recherche Médicale, Unité 478, Faculté de Médecine Xavier Bichat, Institut Fédératif de Recherche 02, 16, rue Henri Bichat, BP416, 75870 Paris Cedex 18, France

The aim of this research was to identify the molecular bases of differences in sensitivity to corticosteroid hormones between Brown Norway and Fischer 344 rats. We previously showed an apparent insensitivity to adrenalectomy in Brown Norway rats. Based on our first hypothesis of a different activity/reactivity of the mineralocorticoid signaling pathway between the two rat strains, we sequenced Brown Norway and Fischer 344 mineralocorticoid receptor cDNA and identified a tyrosine to cysteine substitution (Y73C) in the N-terminal part of the Brown Norway mineralocorticoid receptor. As a first step, this substitution gave us a means to distinguish the Brown Norway allele from the Fischer 344 at the mineralocorticoid receptor locus in an F2 population. We showed a strong genetic linkage between the mineralocorticoid receptor genotype and sensitivity to adrenalectomy. A subsequent genome-wide linkage analysis confirmed the involvement of the mineralocorticoid receptor locus and implicated other loci, including one on chromosome 4, which collectively explain a large part of the strain differences in corticosteroid receptor responses. In vitro studies further revealed that the Y73C substitution induces greater transactivation of the mineralocorticoid receptor by aldosterone, and surprisingly by progesterone as well, which could substitute for aldosterone after adrenalectomy in Brown Norway rats. We challenged this hypothesis in vivo and showed that plasma progesterone is higher in Brown Norway male rats and partially compensates for aldosterone after adrenalectomy. This work illustrates the interest of a pluristrategic approach to explore the mineralocorticoid receptor signaling pathway and its implication in the regulation of hydroelectrolytic homeostasis and blood pressure.

Received for publication, July 2, 2004

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed. Tel.: 33-557-573751; Fax: 33-557-573752; E-mail: marissal{at}bordeaux.inserm.fr.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				N. Marissal-Arvy, A. Gaumont, A. Langlois, F. Dabertrand, M. Bouchecareilh, C. Tridon, and P. Mormede Strain differences in hypothalamic pituitary adrenocortical axis function and adipogenic effects of corticosterone in rats J. Endocrinol., December 1, 2007; 195(3): 473 - 484. [Abstract] [Full Text] [PDF]

				L. Pascual-Le Tallec and M. Lombes The Mineralocorticoid Receptor: A Journey Exploring Its Diversity and Specificity of Action Mol. Endocrinol., September 1, 2005; 19(9): 2211 - 2221. [Abstract] [Full Text] [PDF]