?CaMKII shuttles Ca²?/CaM to the nucleus to trigger CREB phosphorylation and gene expression.

ABSTRACT: 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 Ca(2+)/calmodulin from the surface membrane to the nucleus. We show that the shuttle protein is ?CaMKII, its phosphorylation at Thr287 by ?CaMKII protects the Ca(2+)/CaM signal, and CaN triggers its nuclear translocation. Both ?CaMKII and CaN act in close proximity to CaV1 channels, supporting their dominance, whereas ?CaMKII operates as a carrier, not as a kinase. Upon arrival within the nucleus, Ca(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 CaV1, ?CaMKII, ?CaMKII, and CaN in multiple neuropsychiatric disorders.

SUBMITTER: Ma H 

PROVIDER: S-EPMC4201038 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature