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J. Biol. Chem., Vol. 283, Issue 11, 7109-7116, March 14, 2008

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EF Domains Are Sufficient for Nongenomic Mineralocorticoid Receptor Actions^*

From the Julius-Bernstein-Institut für Physiologie, Universität Halle-Wittenberg, 06097 Halle, Germany

The mineralocorticoid receptor (MR) is important for salt homeostasis and reno-cardiovascular pathophysiology. Signaling mechanisms include, besides classical genomic pathways, nongenomic pathways with putative pathophysiological relevance involving the mitogen-activated protein kinases ERK1/2. We determined the MR domains required for nongenomic signaling and their potential to elicit pathophysiological effects in cultured cells under defined conditions. The expression of full-length human MR or truncated MR consisting of the domains CDEF (MR^CDEF), DEF (MR^DEF), or EF (MR^EF) renders cells responsive for the MR ligand aldosterone with respect to nongenomic ERK1/2 phosphorylation, whereas only full-length MR and MR^CDEF conferred genomic responsiveness. ERK1/2 phosphorylation depends on the EGF receptor and cSRC kinase. MR^EF expression is sufficient to evoke the aldosterone-induced increase of collagen III levels, similar to full-length MR expression. Our data suggest that nongenomic MR signaling is mediated by the EF domains and present the first proof of principle showing that nongenomic signaling can be sufficient for some pathophysiological effects. The minimum amino acid motif required for nongenomic MR signaling and its importance in various effects have yet to be determined.

Received for publication, October 23, 2007 , and in revised form, January 4, 2008.

^* This work was supported by the Deutsche Forschungsgemeinschaft (DFG Grant Ge 905/13-1). 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.

¹ To whom correspondence should be addressed: Julius-Bernstein-Institut für Physiologie, Universität Halle-Wittenberg, Magdeburger Strasse 6, 06097 Halle (Saale), Germany. Tel.: 49-345-557-1886; Fax: 49-345-557-4019; E-mail: michael.gekle{at}medizin.uni-halle.de.

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