Voltage-gated calcium channels (VGCCs) play a crucial role in various cellular processes. These channels consist of different subunits, including the Cavβ subunit. In this study, our focus was to investigate the molecular mechanisms underlying the nuclear trafficking of a specific Cavβ2 splice variant, Cavβ2e, and its potential role in regulating gene expression. Previous reports have demonstrated that electrostatic interactions between positively charged amino acids in the N-terminus of Cavβ2e and negatively charged phospholipids of the plasma membrane facilitate its anchoring to the membrane. Our findings reveal that Cavβ2e can translocate from the plasma membrane to the nucleus upon activation of PLC. Further analysis identified specific amino acids within the N-terminus of Cavβ2e that are essential for its nuclear targeting, acting as a nuclear localization signal. Mutations in these amino acids resulted in reduced nuclear localization, supporting their involvement in the nuclear translocation of Cavβ2e. We also investigated the presence of a nuclear export signal within Cavβ2e and identified a crucial dileucine motif that is involved in its trafficking between the nucleus and cytosol. Moreover, we studied the function of nuclear Cavβ2e and found that it potentially can regulate gene expression. In conclusion, our study provides insights into the potential regulation of gene expression in native systems through the translocation of Cavβ2e from the plasma membrane to the nucleus upon activation of PLC.