γCaMKII Shuttles Ca2+/CaM to the Nucleus to Trigger CREB Phosphorylation and Gene Expression

Activity-dependent CREB phosphorylation and gene expression are critical for long-term neuronal plasticity. Local signaling at CaV1 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 CaV1 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 CaV1, γCaMKII, βCaMKII, and CaN in multiple neuropsychiatric disorders. [Display omitted] •Ca2+/CaM near CaV1 channels is delivered into the nucleus by γCaMKII•Ca2+/CaM provides the crucial signal to activate transcription factor CREB•βCaMKII phosphorylates γCaMKII at Thr287 to protect the Ca2+/CaM signal•CaN dephosphorylates γCaMKII at Ser334 to trigger γCaMKII nuclear translocation Electrical activity at the neuronal membrane initiates gene transcription through the action of γCaMKII that shuttles Ca2+/CaM from cell surface to the nucleus. Upon arrival, Ca2+/CaM activates a nuclear CaMK cascade that phosphorylates CREB and sparks expression of c-fos and other genes.