Transcriptional regulation of T-type calcium channel CaV3.2: Bi-directionality by early growth response 1 (Egr1) and repressor element 1 (RE-1) protein -silencing transcription factor (REST)

Karen M.J. Van Loo*, Christina Schaub, Katharina Pernhorst, Yoel Yaari, Heinz Beck, Susanne Schoch, Albert J. Becker

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

57 Scopus citations

Abstract

The pore-forming Ca2+ channel subunit CaV3.2 mediates a low voltage-activated (T-type) Ca2+ current (ICaT) that contributes pivotally to neuronal and cardiac pacemaker activity. Despite the importance of tightly regulated CaV3.2 levels, the mechanisms regulating its transcriptional dynamics are not well understood. Here, we have identified two key factors that upand down-regulate the expression of the gene encoding CaV3.2 (Cacna1h). First, we determined the promoter region and observed several stimulatory and inhibitory clusters. Furthermore, we found binding sites for the transcription factor early growth response 1 (Egr1/Zif268/Krox-24) to be highly overrepresented within the CaV3.2 promoter region. mRNA expression analyses and dual-luciferase promoter assays revealed that the CaV3.2 promoter was strongly activated by Egr1 overexpression in vitro and in vivo. Subsequent chromatin immunoprecipitation assays in NG108-15 cells and mouse hippocampi confirmed specific Egr1 binding to the CaV3.2 promoter. Congruently, whole-cell ICaT values were significantly larger after Egr1 overexpression. Intriguingly, Egr1-induced activation of the CaV3.2 promoter was effectively counteracted by the repressor element 1-silencing transcription factor (REST). Thus, Egr1 and REST can bi-directionally regulate CaV3.2 promoter activity and mRNA expression and, hence, the size of ICaT. This mechanism has critical implications for the regulation of neuronal and cardiac Ca2+ homeostasis under physiological conditions and in episodic disorders such as arrhythmias and epilepsy.

Original languageEnglish
Pages (from-to)15489-15501
Number of pages13
JournalJournal of Biological Chemistry
Volume287
Issue number19
DOIs
StatePublished - 4 May 2012

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