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 Ca(2+) signalling generated by cardiac T-type current (I(CaT)) and RAAS signalling. Neonatal rat cardiomyocytes exposed to aldosterone, angiotensin II or aldosterone plus angiotensin II co-treatment (AA) show an increase in I(CaT) density, with no cumulative effect of the AA co-treatment. AA increases the amount of T-type channel Ca(v)3.1 mRNA in a time-dependent manner. Angiotensin II increases Ca(v)3.1 mRNA stability, whereas aldosterone increases the transcriptional activity of the Ca(v)3.1 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 Ca(v)3.1 mRNA and MEK1/2 promoted CREB-target gene transcription. Aldosterone and AA-induced I(CaT) 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 I(CaT) 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 I(CaT) 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.
Dept Recherche Médicale, Remodelage Tissulaire et Fonctionnel: Signalisation et Physiopathologie, CNRS-UMR8162, INSERM-U999, Université Paris-Sud XI, Hôpital Marie Lannelongue, Le Plessis Robinson, France.
Yann
Y
Ruchon
Laurent
L
Ferron
Safietou
S
Sankhe
Jean-François
JF
Renaud
Véronique
V
Capuano
D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D005444:Flunarizine / Q000494:pharmacology; D005473:Fluoxetine / Q000494:pharmacology; D048369:MAP Kinase Kinase 1 / Q000378:metabolism*; D048370:MAP Kinase Kinase 2 / Q000378:metabolism*; D008297:Male; D020748:Mibefradil / Q000494:pharmacology; D015735:Mifepristone / Q000494:pharmacology; D000451:Mineralocorticoid Receptor Antagonists; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism*; D009543:Nifedipine / Q000494:pharmacology; D010766:Phosphorylation; D051381:Rats; D017208:Rats, Wistar; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors; D012084:Renin-Angiotensin System / Q000235:genetics*; D013148:Spironolactone / Q000494:pharmacology
D000451:Mineralocorticoid Receptor Antagonists; D011965:Receptors, Glucocorticoid; D005473:Fluoxetine; D020748:Mibefradil; D013148:Spironolactone; D015735:Mifepristone; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; D009543:Nifedipine; D005444:Flunarizine