Translocation of calmodulin to the nucleus supports CREB phosphorylation in hippocampal neurons


Activation of the transcription factor CREB is thought to be important in the formation of long-term memory in several animal species1,2,3. The phosphorylation of a serine residue at position 133 of CREB is critical for activation of CREB4. This phosphorylation is rapid when driven by brief synaptic activity in hippocampal neurons5. It is initiated by a highly local, rise in calcium ion concentration5 near the cell membrane, but culminates in the activation of a specific calmodulin-dependent kinase known as CaMK IV (ref. 7), which is constitutively present in the neuronal nucleus7,8. It is unclear how the signal is conveyed from the synapse to the nucleus. We show here that brief bursts of activity cause a swift (1 min) translocation of calmodulin from the cytoplasm to the nucleus, and that this translocation is important for the rapid phosphorylation of CREB. Certain Ca2+ entry systems (L-type Ca2+ channels and NMDA receptors) are able to cause mobilization of calmodulin, whereas others (N- and P/Q-type Ca2+ channels) are not. This translocation of calmodulin provides a form of cellular communication that combines the specificity of local Ca2+ signalling with the ability to produce action at a distance.

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Figure 1: Rapid activity-dependent translocation of calmodulin to the nucleus in hippocampal CA3/CA1 pyramidal neurons.
Figure 2: Selective control of activity-dependent CaM translocation by NMDA receptors and L-type Ca2+ channels.
Figure 3: Close relationship between activity-dependent CaM translocation and CREB phosphorylation.
Figure 4: Requirement for nuclear CaM translocation in activity-dependent CREBphosphorylation.
Figure 5: Causal link between nuclear CaM and activity-dependent CREB phosphorylation in hippocampal neurons.


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We thank A. Nairn for antibodies; J. Dedman, J. Wang and M. Kaetzel for nCaMBP reagents; D. L. Taylor and J. Montibeller for mCaM; H. Schulman and H. Bito for advice and for comments on the manuscript; and R. Lewis, T. Schwarz and L. Stryer for comments on the manuscript. Supported by grants from the Silvio Conte-NIMH Center for Neuroscience Research, the McKnight Foundation, the Mathers Charitable Trust, and the NIH Medical Scientist Training Program.

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Correspondence to Richard W. Tsien.

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