gamma CaMKII Shuttles Ca super(2+)/CaM to the Nucleus to Trigger CREB Phosphorylation and Gene Expression

• Published in: Cell Vol. 159; no. 2; pp. 281 - 294
• Main Authors: Ma, Huan, Groth, Rachel D, Cohen, Samuel M, Emery, John F, Li, Boxing, Hoedt, Esthelle, Zhang, Guoan, Neubert, Thomas A, Tsien, Richard W
• Format: Journal Article
• Language: English
• Published: 09.10.2014
• ISSN: 0092-8674
• DOI: 10.1016/j.cell.2014.09.019

Activity-dependent CREB phosphorylation and gene expression are critical for long-term neuronal plasticity. Local signaling at Ca sub(V)1 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 Ca super(2+)/calmodulin from the surface membrane to the nucleus. We show that the shuttle protein is gamma CaMKII, its phosphorylation at Thr287 by beta CaMKII protects the Ca super(2+)/CaM signal, and CaN triggers its nuclear translocation. Both beta CaMKII and CaN act in close proximity to Ca sub(V)1 channels, supporting their dominance, whereas gamma CaMKII operates as a carrier, not as a kinase. Upon arrival within the nucleus, Ca super(2+)/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 sub(V)1, gamma CaMKII, beta CaMKII, and CaN in multiple neuropsychiatric disorders.