C-Terminus of Ca_v1.3 L-Type Ca²⁺ Channel Upregulates Its Own Gene Expression

The Ca_v1.3 L-type calcium (Ca²⁺) channel plays a critical role in cardiac excitation-contraction coupling, regulating heart rate, contractility, and gene expression. The C-terminus of Ca_v1.3 has recently been shown to translocate to the nucleus and act as a transcriptional factor to modulate the function of Ca²⁺-activated K⁺ channels in atrial cardiomyocytes. However, the role of the Ca_v1.3-C-terminus in the regulation of transcription of its own Ca_v1.3 gene remains unknown. We evaluated the impact of the nuclear translocation of the Ca_v1.3-C-terminus on the transcription of the Ca_v1.3 gene and Ca_v1.3 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_v1.3-C-terminus translocates to the nucleus where it acts as a trans-regulator. The C-terminus of Ca_v1.3 increased transcription of Ca_v1.3 in vitro in NRVMs and in vivo in mice ventricles. Additionally, MEF2 transcription factor binding sites within the Ca_v1.3 promoter may contribute to the regulatory effect of the Ca_v1.3-C-terminus. These data are the first to demonstrate unique upregulation of Ca_v1.3 transcription by its own mobile Ca_v1.3-C-terminus both in vitro and in vivo. These findings suggest that the Ca_v1.3-C-terminus has intrinsic properties as a trans-regulator of gene expression and may contribute to the modulation of cardiac function.