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, IC(50), approximately 0.3 nM) inhibits CREB transcriptional activity induced by stimulation of beta1/2-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(S133) phosphorylation via calcineurin/PP2B activation without changes in PP2B-Aalpha 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
Claudia
C
Julius-Bernstein-Institut für Physiologie, Universität Halle-Wittenberg, Halle, Germany.
Wuttke
Martin
M
Ruhs
Stefanie
S
Seiferth
Anja
A
Mildenberger
Sigrid
S
Rabe
Sindy
S
Schwerdt
Gerald
G
Gekle
Michael
M
D001011:Aorta / Q000166:cytology / Q000378:metabolism*; D015153:Blotting, Western; D019703:Calcineurin / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D051786:Cyclic AMP Response Element Modulator / Q000235:genetics / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005954:Glucosephosphate Dehydrogenase / Q000378:metabolism; D006801:Humans; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D010766:Phosphorylation; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011941:Receptors, Adrenergic / Q000378:metabolism; D018161:Receptors, Mineralocorticoid / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction
C497410:CREM protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D012333:RNA, Messenger; D011941:Receptors, Adrenergic; D018161:Receptors, Mineralocorticoid; D051786:Cyclic AMP Response Element Modulator; D000242:Cyclic AMP; D005954:Glucosephosphate Dehydrogenase; D019703:Calcineurin