期刊
JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY
卷 178, 期 -, 页码 193-202出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jsbmb.2017.12.013
关键词
T-type channels; Cardiomyocytes; Glucocorticoids; Glucocorticoid receptor; Transcription
资金
- Ministerio de Economia y Competitividad [SAF2013-46806-R]
- Proyecto de Excelencia of the Consejeria de Innovacion y Ciencia de la Junta de Andalucia [CTS-7045]
- Red de Investigacitin Cardiovascular from the Ministerio de Economia y Competitividad, ISCIII [RIC RD12/0042/0041]
- FEDER funds
- Universidad de Sevilla
Glucocorticoids are widely used to treat acute and chronic diseases. Unfortunately, their therapeutic use is associated with severe side effects. Glucocorticoids are known to regulate several ion channels in cardiac myocytes, including voltage-dependent Ca2+ channels. Low-voltage-activated T-type Ca2+ channels are expressed in ventricular myocytes during the fetal and perinatal period, but are practically absent in the adult. However, these channels can be re-expressed in adult cardiomyocytes under some pathological conditions. We have investigated the glucocorticoid regulation of T-type Ca2+ channels in rat cardiomyocytes. Molecular studies revealed that dexamethasone induces the upregulation of Ca(v)3.2 mRNA in neonatal rat ventricular myocytes, whereas Ca(v)3.1 mRNA is only slightly affected. Patch-clamp recordings confirmed that T-type Ca2+ channel currents were upregulated in dexamethasone treated cardiomyocytes, and the addition of 50 mu mol/L NiCl2 demonstrated that the Ca(v)3.2 channel is responsible for this upregulation. The effect of dexamethasone on Ca(v)3.2 is mediated by the activation and translocation to the cell nucleus of the glucocorticoid receptor (GR). We have isolated the upstream promoter of the Cacna1h gene and tested its activity in transfected ventricular myocytes. The initial in silico analysis of Cacna1h promoter revealed putative glucocorticoid response elements (GREs). Transcriptional activity assays combined with deletion analyses and chromatin immunoprecipitation assays demonstrated that GR binds to a region a GRE located in -1006/-985 bp of Cacna1h promoter. Importantly, upregulation of the Ca(v)3.2 channel is also observed in vitro in adult rat ventricular myocytes, and in vivo in a rat model of excess of glucocorticoids.
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