Key result
Egr1 overexpression strongly activated the Ca(V)3.2 promoter and significantly increased whole-cell T-type Ca(2+) currents, an effect that was effectively counteracted by REST.
Egr1 and REST bi-directionally regulate CaV3.2 expression, providing a mechanistic basis for T-type calcium channel regulation relevant to cardiac pacemaker activity and arrhythmias.
May modulate pacemaker activity via T-type currents; hypothesis-generating for arrhythmia mechanisms, needs human validation.
The pore-forming Ca(2+) channel subunit Ca(V)3.2 mediates a low voltage-activated (T-type) Ca(2+) current (I(CaT)) that contributes pivotally to neuronal and cardiac pacemaker activity. Despite the importance of tightly regulated Ca(V)3.2 levels, the mechanisms regulating its transcriptional dynamics are not well understood. Here, we have identified two key factors that up- and down-regulate the expression of the gene encoding Ca(V)3.2 (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 Ca(V)3.2 promoter region. mRNA expression analyses and dual-luciferase promoter assays revealed that the Ca(V)3.2 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 Ca(V)3.2 promoter. Congruently, whole-cell I(CaT) values were significantly larger after Egr1 overexpression. Intriguingly, Egr1-induced activation of the Ca(V)3.2 promoter was effectively counteracted by the repressor element 1-silencing transcription factor (REST). Thus, Egr1 and REST can bi-directionally regulate Ca(V)3.2 promoter activity and mRNA expression and, hence, the size of I(CaT). This mechanism has critical implications for the regulation of neuronal and cardiac Ca(2+) homeostasis under physiological conditions and in episodic disorders such as arrhythmias and epilepsy.
No takes yet. Share an insight, caveat, or question.
Loo et al. (2012) studied Neuronal and cardiac Ca(2+) homeostasis (arrhythmias and epilepsy). Egr1 overexpression vs. REST (repressor element 1-silencing transcription factor) was evaluated on Ca(V)3.2 promoter activity, mRNA expression, and whole-cell I(CaT) values. Egr1 overexpression strongly activated the Ca(V)3.2 promoter and significantly increased whole-cell T-type Ca(2+) currents, an effect that was effectively counteracted by REST.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: