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

• 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

SummaryActivity-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.

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