T-type Ca2 + signalling downregulates MEK1/2 phosphorylation and cross-talk with the RAAS transcriptional response in cardiac myocytes

Cardiac dysfunction is often associated with an increase in the activity of the renin–angiotensin II–aldosterone system (RAAS). Here, we highlight the cross-talk between the Ca2 + signalling generated by cardiac T-type current (ICaT) and RAAS signalling.Neonatal rat cardiomyocytes exposed to aldosterone, angiotensin II or aldosterone plus angiotensin II co-treatment (AA) show an increase in ICaT density, with no cumulative effect of the AA co-treatment. AA increases the amount of T-type channel Cav3.1 mRNA in a time-dependent manner. Angiotensin II increases Cav3.1 mRNA stability, whereas aldosterone increases the transcriptional activity of the Cav3.1 gene promoter. However, in AA-treated cells, angiotensin II decreases aldosterone-induced promoter activity, and aldosterone decreases angiotensin II-induced mRNA stability. The mitogen-activated protein kinase kinase (MEK1/2), which is synergically phosphorylated in AA-treated cells, alters the translocation of glucocorticoid receptors (GR) into the nucleus and attenuates aldosterone-induced promoter activity. In contrast, MEK1/2 has no effect on the NFkB-induced increase in Cav3.1 mRNA and MEK1/2 promoted CREB-target gene transcription. Aldosterone and AA-induced ICaT signalling result in a time-dependent activation of the phosphatase PP2A, which dephosphorylates MEK1/2 and CREB. Finally, angiotensin II alone also activates PP2A, which targets MEK1/2, but this activation is independent of ICaT calcium signalling and has no effect on CREB phosphorylation.In conclusion, our data demonstrate the cross-talk between a GR-mediated aldosterone response, angiotensin II and the ICaT signalling pathways and identify MEK1/2 as a point of connection. This cross-talk results in the fine control of GR- and/or CREB-target gene expression.

► Calcium signalling changes following hormones stimulation.
► Translocation of glucocorticoid receptors into the nucleus depends on phosphorylation.
► We examine a mechanism of two hormones interconnected pathways.
► We propose a mechanism that occur during heart pathology.