Calcium channel-coupled transcription factors facilitate direct nuclear signaling

VGCCs play crucial roles within the CNS, in maintaining cell excitability, enabling activity-dependent neuronal development, and forming long-term memory by regulating Ca²⁺ influx. The intracellular carboxyl-terminal domains of VGCC α1 subunits help regulate VGCC function. Emerging evidence suggests that some VGCC C-termini have functions independent of channel gating and exist as stable proteins. Here, we demonstrate that all VGCC gene family members express bicistronic mRNA transcripts that produce functionally distinct C-terminal proteins (CTPs) in tandem with full-length VGCC α1 subunits. Two of these CTPs, α1CCT and α1ACT, cycle to and from the nucleus in a Ca²⁺- and calmodulin-dependent fashion. α1CCT, α1ACT, and α1HCT regulate chromatin accessibility and/or bind directly to genes, regulating gene networks involved in neuronal differentiation and synaptic function in a Ca²⁺-dependent manner. This study elucidates a conserved process of coordinated protein expression within the VGCC family, coupling the channel function with VGCC C-terminal transcription factors.