title: EF domains are sufficient for nongenomic mineralocorticoid receptor actions.
abstract: 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.
authors.affiliation: Julius-Bernstein-Institut für Physiologie, Universität Halle-Wittenberg, 06097 Halle, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Grossmann
authors.forename: Ruth
authors.initials: R
authors.lastname: Freudinger
authors.forename: Sigrid
authors.initials: S
authors.lastname: Mildenberger
authors.forename: Britta
authors.initials: B
authors.lastname: Husse
authors.forename: Michael
authors.initials: M
authors.lastname: Gekle
mesh_terms: D000450:Aldosterone / Q000378:metabolism* / Q000494:pharmacology; D020816:Amino Acid Motifs; D000596:Amino Acids / Q000737:chemistry; D000818:Animals; D003094:Collagen / Q000737:chemistry / Q000378:metabolism*; D006224:Cricetinae; D005786:Gene Expression Regulation; D006801:Humans; D008024:Ligands; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D008954:Models, Biological; D017434:Protein Structure, Tertiary; D018161:Receptors, Mineralocorticoid / Q000737:chemistry* / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D000596:Amino Acids; D008024:Ligands; D018161:Receptors, Mineralocorticoid; D000450:Aldosterone; D003094:Collagen; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3