Mineralocorticoid receptor inhibits CREB signaling by calcineurin activation

We investigated the interaction of MR with cAMP-response element binding protein (CREB) and provide a mechanistic explanation and insights into the cellular relevance. MR → CREB crosstalk was assessed in vascular smooth muscle cells and heterologous expression systems. Experiments were designed in a way that only one variable changed at a time and the respective vehicles served as controls. MR, but not GR, activation (aldosterone or hydrocortisone, IC50, ~0.3 nM) inhibits CREB transcriptional activity induced by stimulation of ß1/2-adrenoceptors and adenylyl cyclase or addition of membrane-permeable cAMP up to 70% within 2 h after addition. The MR DNA-binding domain is not required for this inhibition. cAMP formation is virtually unchanged, whereas MR exerts a robust inhibition of CREB phosphorylation via calcineurin/ PP2B activation without changes in PP2B-Aα or ß expression. In parallel, the PP2B-sensitive NFaT-path-way is activated. The inhibitory crosstalk attenuates CREB-induced glucose-6-phosphate dehydrogenase expression. Overall, transcriptional relevant MR → CREB crosstalk occurs at the level of CREB phosphorylation by enhanced calcineurin activity, enables GRE-independent genomic signaling of MR, and is of potential pathophysiological relevance.—Grossmann, C, Wuttke, M., Ruhs, S., Seiferth, A., Mildenberger, S., Rabe, S., Schwerdt, G., Gekle, M. Mineralocorticoid receptor inhibits CREB signaling by calcineurin activation. FASEB J. 24, 2010–2019 (2010). www.fasebj.org