Regulation of T-type Cav3.1 channels expression by synthetic glucocorticoid dexamethasone in neonatal cardiac myocytes.
The effect of the dexamethasone (Dex) on the regulation of the T-type Ca(2+) channel expressions was investigated in primary cultures of neonatal rat ventricular myocytes. We found that Dex (1 microM) increases the T-type Ca(2+) current (I(CaT)) associated with an increase in Ca(v)3.1 mRNA amount. We isolated the upstream region from Ca(v)3.1 encoding gene and tested the activity of the promoter in transfected ventricular myocytes. We found a minimal Dex-responsive region that displayed putative glucocorticoid receptor (GR) and nuclear factor kappa-B (NFkappaB) targets. The GR selective antagonist, RU38486 (10 microM), nearly turned off the transcriptional activity of Ca(v)3.1 encoding gene, and an NFkappaB inhibitor, pyrrolodine dithiocarbonate (10 microM), completely abolished the Dex-induced mRNA increase. However, Dex-induced GR and NFkappaB synthesis and nuclear translocation were not timely related to Ca(v)3.1 mRNA increase. These results indicate that both GR and NFkappaB were necessary, but not sufficient, to trigger the increase in Ca(v)3.1 mRNA amount. This study showed the relationship between glucocorticoid and T-type channels up-regulation that may be involved in cardiac development and pathology.
BenMohamed
Fatima
F
CNRS UMR 8162 - Université Paris-Sud XI, Hôpital Marie Lannelongue, 133 avenue de Résistance, 92350 Le Plessis Robinson, France. fatima.ben-mohamed@u-psud.fr
Ferron
Laurent
L
Ruchon
Yann
Y
Gouadon
Elodie
E
Renaud
Jean-François
JF
Capuano
Véronique
V
D000818:Animals; D000831:Animals, Newborn; D001483:Base Sequence; D020747:Calcium Channels, T-Type / Q000235:genetics / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology*; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects*; D005938:Glucocorticoids / Q000494:pharmacology*; D006727:Hormone Antagonists / Q000494:pharmacology; D006801:Humans; D015735:Mifepristone / Q000494:pharmacology; D008969:Molecular Sequence Data; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000502:physiology; D016328:NF-kappa B / Q000378:metabolism; D018408:Patch-Clamp Techniques; D051381:Rats; D017208:Rats, Wistar; D011965:Receptors, Glucocorticoid / Q000378:metabolism
C500994:Cacna1g protein, rat; D020747:Calcium Channels, T-Type; D005938:Glucocorticoids; D006727:Hormone Antagonists; D016328:NF-kappa B; D011965:Receptors, Glucocorticoid; D015735:Mifepristone; D003907:Dexamethasone