Calcium channel-coupled transcription factors facilitate direct nuclear signaling

Abstract

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 1 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 1 subunits. Two of these CTPs, 1CCT and 1ACT, cycle to and from the nucleus in a Ca2+- and calmodulin-dependent fashion. 1CCT, 1ACT, and 1HCT 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.