Activity-dependent CREB phosphorylation and gene expression are critical for long-term neuronal plasticity. Local signaling at Ca_V1 channels triggers these events, but how information is relayed onward to the nucleus remains unclear. Here, we report a mechanism that mediates long-distance communication within cells: a shuttle that transports Ca²⁺/calmodulin from the surface membrane to the nucleus. We show that the shuttle protein is γCaMKII, its phosphorylation at Thr287 by βCaMKII protects the Ca²⁺/CaM signal, and CaN triggers its nuclear translocation. Both βCaMKII and CaN act in close proximity to Ca_V1 channels, supporting their dominance, whereas γCaMKII operates as a carrier, not as a kinase. Upon arrival within the nucleus, Ca²⁺/CaM activates CaMKK and its substrate CaMKIV, the CREB kinase. This mechanism resolves long-standing puzzles about CaM/CaMK-dependent signaling to the nucleus. The significance of the mechanism is emphasized by dysregulation of Ca_V1, γCaMKII, βCaMKII, and CaN in multiple neuropsychiatric disorders.