Evidence for a functional interaction between calmodulin and the glucocorticoid receptor

Area of Science:

• Molecular Biology
• Cell Signaling
• Endocrinology

Background:

• Calmodulin (CaM) is crucial in membrane-bound receptor signaling.
• The role of CaM in intracellular steroid receptor activation remains largely unknown.
• Steroid receptors, like the glucocorticoid receptor (GR), are ligand-regulated transcription factors.

Purpose of the Study:

• To investigate the role of calmodulin (CaM) in the activation of intracellular steroid receptors.
• To determine if CaM interacts with the glucocorticoid receptor (GR) complex.
• To assess the effect of CaM antagonists on GR-mediated gene expression.

Main Methods:

• Investigated CaM interaction with the untransformed GR complex containing hsp90 in a calcium-dependent manner.
• Utilized four unrelated CaM antagonists: trifluoperazine, compound 48/80, W7, and phenoxybenzamine.
• Assessed inhibition of GR-mediated gene expression in mouse L929 cells with a stably-transfected MMTV-CAT reporter gene.

Main Results:

• Demonstrated a calcium-dependent interaction between CaM and the untransformed GR complex (including hsp90).
• Showed that four different CaM antagonists significantly inhibit GR-mediated gene expression.
• Observed this inhibition in mouse L929 cells using the MMTV-CAT reporter gene system.

Conclusions:

• Calmodulin (CaM) plays a significant role in the signal transduction pathways of steroid hormone receptors.
• CaM interaction with the glucocorticoid receptor (GR) complex is a key step in GR activation.
• CaM antagonists represent potential modulators of steroid hormone receptor signaling.