C-Terminus of Cav1.3 L-Type Ca2+ Channel Upregulates Its Own Gene Expression

Introduction: Ca v 1.3 L‐type calcium (Ca 2+ ) channel plays a critical role in cardiac excitation-contraction coupling, regulating heart rate, contractility, and gene expression. The C-terminus of Ca v 1.3 has recently been shown to translocate to the nucleus and act as a transcriptional factor to modulate the function of Ca 2+ activated K + channels in atrial cardiomyocytes. However, the role of Ca v 1.3-C-terminus in the regulation of transcription of its own Ca v 1.3 gene remains unknown. Methods and Results : We evaluated the impact of the nuclear translocation of Ca v 1.3-C-terminus on the transcription of Ca v 1.3 gene and Ca v 1.3 promoter activity in vitro using cultured neonate rat ventricular myocytes (NRVMs), and mouse atrial cardiomyocytes (HL-1). Lentiviral infection of NRVMs demonstrated that the cleaved Ca v 1.3-C-terminus, translocate to the nucleus where it acts as an enhancer. C-terminus of Ca v 1.3 increased transcription of Ca v 1.3 in vitro in NRVMs and in vivo in mice ventricles. Additionally, MEF2 transcription factor binding sites along the Ca v 1.3 promoter seemed to mediate the regulatory effect of the Ca v 1.3-C-terminus. Conclusion: The data are first to demonstrate unique upregulation of Ca v 1.3 transcription by its own mobile Ca v 1.3-C‐terminus both in vitro and in vivo . These novel findings are directly translatable to the development of new therapeutics aimed at increasing Ca 2+ entry into the cells via intrinsic Ca v 1.3 gene expression upregulation such as in heart failure where additional and optimal Ca 2+ entry could be beneficial.