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, similar to 0.3 nM) inhibits CREB transcriptional activity induced by stimulation of beta 1/2-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 CREBS133 phosphorylation via calcineurin/PP2B activation without changes in PP2B-A alpha or beta expression. In parallel, the PP2B-sensitive NFaT-pathway 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