gamma CaMKII Shuttles Ca super(2+)/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 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 comm...
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Published in | Cell Vol. 159; no. 2; pp. 281 - 294 |
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Main Authors | , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
09.10.2014
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Online Access | Get full text |
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Summary: | 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. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 content type line 23 ObjectType-Feature-2 |
ISSN: | 0092-8674 |
DOI: | 10.1016/j.cell.2014.09.019 |