Cytosolic peptides encoding Ca1 C-termini downregulate the calcium channel activity-neuritogenesis coupling.

L-type Ca (Ca1) channels transduce channel activities into nuclear signals critical to neuritogenesis. Also, standalone peptides encoded by Ca1 DCT (distal carboxyl-terminus) act as nuclear transcription factors reportedly promoting neuritogenesis. Here, by focusing on exemplary Ca1.3 and cortical neurons under basal conditions, we discover that cytosolic DCT peptides downregulate neurite outgrowth by the interactions with Ca1's apo-calmodulin binding motif. Distinct from nuclear DCT, various cytosolic peptides exert a gradient of inhibitory effects on Ca influx via Ca1 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 Ca-sensitive nuclear retention of DCT. In summary, DCT peptides as a class of Ca1 inhibitors specifically regulate the channel activity-neuritogenesis coupling in a variant-, affinity-, and localization-dependent manner.