Cytosolic peptides encoding Ca_V1 C-termini downregulate the calcium channel activity-neuritogenesis coupling

L-type Ca²⁺ (Ca_V1) channels transduce channel activities into nuclear signals critical to neuritogenesis. Also, standalone peptides encoded by Ca_V1 DCT (distal carboxyl-terminus) act as nuclear transcription factors reportedly promoting neuritogenesis. Here, by focusing on exemplary Ca_V1.3 and cortical neurons under basal conditions, we discover that cytosolic DCT peptides downregulate neurite outgrowth by the interactions with Ca_V1’s apo-calmodulin binding motif. Distinct from nuclear DCT, various cytosolic peptides exert a gradient of inhibitory effects on Ca²⁺ influx via Ca_V1 channels and neurite extension and arborization, and also the intermediate events including CREB activation and c-Fos expression. The inhibition efficacies of DCT are quantitatively correlated with its binding affinities. Meanwhile, cytosolic inhibition tends to facilitate neuritogenesis indirectly by favoring Ca²⁺-sensitive nuclear retention of DCT. In summary, DCT peptides as a class of Ca_V1 inhibitors specifically regulate the channel activity-neuritogenesis coupling in a variant-, affinity-, and localization-dependent manner.