The mineralocorticoid receptor (MR) is important for salt homeostasis and renocardiovascular pathophysiology. Signaling mechanisms include beside classical genomic pathways also nongenomic pathways with putative pathophysiological relevance, involving mitogen-activated protein kinases ERK1/2. We determined MR-domains required for nongenomic signaling and their potential to elicit pathophysiological effects in cultured cells under defined conditions. Expression of full length human MR or truncated MR consisting of the domains CDEF (MRCDEF), DEF (MRDEF) or EF (MREF) renders cells responsive for the MR-ligand aldosterone with respect to nongenomic ERK1/2-phopshorylation, whereas only full length MR and MRCDEF conferred genomic responsiveness. ERK1/2- phopsphorylation depends on EGF receptor and cSRC kinase. MREF expression is sufficient to evoke the aldosterone induced increase of collagen III abundance 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 for the various effects has to be determined.