Format

Send to

Choose Destination
Cell. 2014 Oct 9;159(2):281-94. doi: 10.1016/j.cell.2014.09.019.

γCaMKII shuttles Ca²⁺/CaM to the nucleus to trigger CREB phosphorylation and gene expression.

Author information

1
Department of Neuroscience and Physiology, Neuroscience Institute, NYU Langone Medical Center, New York, NY 10016, USA. Electronic address: mahuan@gmail.com.
2
Centers for Therapeutic Innovation, Pfizer, 1700 Owens Street, San Francisco, CA 94158, USA.
3
Department of Neuroscience and Physiology, Neuroscience Institute, NYU Langone Medical Center, New York, NY 10016, USA.
4
Department of Biochemistry and Molecular Pharmacology and Skirball Institute, NYU Langone Medical Center, New York, NY 10016, USA.
5
Department of Neuroscience and Physiology, Neuroscience Institute, NYU Langone Medical Center, New York, NY 10016, USA. Electronic address: richard.tsien@nyumc.org.

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 γCaMKII, its phosphorylation at Thr287 by βCaMKII protects the Ca(2+)/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, 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, γCaMKII, βCaMKII, and CaN in multiple neuropsychiatric disorders.

PMID:
25303525
PMCID:
PMC4201038
DOI:
10.1016/j.cell.2014.09.019
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center