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Mineralocorticoid receptor inhibits CREB signaling by calcineurin activation

Claudia Grossmann1, Martin Wuttke, Stefanie Ruhs

  • 1Julius-Bernstein-Institut für Physiologie, Universität Halle-Wittenberg, Halle, Germany.

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology
|January 28, 2010
PubMed

Insights

Mineralocorticoid receptor (MR) activation inhibits cAMP-response element binding protein (CREB) activity by blocking CREB phosphorylation. This crosstalk, mediated by calcineurin, impacts gene expression and has potential pathophysiological relevance.

Area of Science:

  • Endocrinology
  • Molecular Biology
  • Cellular Signaling

Background:

  • Mineralocorticoid receptor (MR) and cAMP-response element binding protein (CREB) are key regulators of cellular processes.
  • Understanding the crosstalk between MR and CREB is crucial for elucidating complex signaling pathways.

Purpose of the Study:

  • To investigate the interaction between MR and CREB.
  • To provide a mechanistic explanation for MR-CREB crosstalk and its cellular relevance.

Main Methods:

  • Experiments were conducted in vascular smooth muscle cells and heterologous expression systems.
  • MR and Glucocorticoid Receptor (GR) activation was assessed using aldosterone and hydrocortisone.
  • CREB transcriptional activity, phosphorylation, and downstream gene expression were measured.
  • Calcineurin and Protein Phosphatase 2B (PP2B) activity were analyzed.

Main Results:

  • MR activation, but not GR, significantly inhibited CREB transcriptional activity.
  • MR inhibited CREB(S133) phosphorylation via enhanced calcineurin/PP2B activity, independent of the MR DNA-binding domain.
  • cAMP formation remained unchanged, while the PP2B-sensitive NFaT-pathway was activated.
  • This inhibitory crosstalk attenuated CREB-induced glucose-6-phosphate dehydrogenase expression.

Conclusions:

  • MR-CREB crosstalk occurs at the level of CREB phosphorylation, mediated by increased calcineurin activity.
  • This interaction enables GRE-independent genomic signaling by MR.
  • The identified MR-CREB crosstalk mechanism holds potential pathophysiological significance.

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