Opposing neural signals of CaV1-encoded peptides are tuned by C-terminus mediated inhibition

L-type calcium (CaV1) channels regulate gene expressions via the cascade of excitation-transcription coupling, or directly as standalone CCAT (Calcium Channel Associated Transcriptional-regulator) peptides encoding distal carboxyl-terminus (DCT) of CaV1, both evidenced in dendritogenesis signaling in neurons. We here discover that DCT peptides opposedly mediate these two sets of transcription signals, all tunable in accordance to C-terminus mediated inhibition (CMI) of Ca2+/CaV1 influx. By electrophysiology, neurite morphology, and FRET 2-hybrid binding analyses, we systematically examined native and derived DCT peptides across CaV1, unveiling that the overall balance between cytosolic inhibition versus nuclear facilitation is spatially and temporally tuned by CMI of each DCT variant. Our findings not only resolve several controversies existing to DCT variants, but also propose a de novo scheme of CaV1-centric gene regulation: two concurrent routes of transcription signals initiated from either membrane CaV1 channels or nuclear CaV1-encoded peptides are subject to autonomous feedback tuning by peptide/channel interactions.