Neuronal Ca2+ entry via voltage-gated Ca2+ channels and NMDA receptor Channels provides a critical link between synaptic activity and changes in gene expression. Despite the importance of communication from synapse to nucleus, relatively little is known about basic mechanisms. A key target of such signaling is the nuclear transcription factor CREB undergoes phosphorylation at Ser133, it can turn on transcription and thereby activate a host of CRE-dependent genes. Recently, our group has uncovered a novel signal transduction pathway that links CA2+ entry to rapid (<1 min) CREB phosphorylation. The signaling is initiated by opening of L-type (but not P/Q or N-type) CA2+ channels, and depends critically on the translocation of calmodulin from sites near the surface membrane to within the nucleus itself, where it activates nuclear CaMKIV, a potent CREB kinase. In this project, the investigators propose to study cellular and molecular aspects of the synapse t nucleus signaling. What gives L-type channels the specific ability to initiate CaM translocation? What are the spatiotemporal properties of CaM signaling following general or focal stimulation? What molecular mechanisms support translocation of CaM to the nucleus and stabilization of its Ca2+-bound form? How do the multiple targets of CaM (e.g. kinase kinase, kinase, phosphatase) interact together to control CREB phosphorylation levels and downstream gene expression? What are the consequences of disrupting fast CaM signaling in hippocampal slices? The investigators will approach these questions as an extension of our long-term interest in the functional impact of diverse Ca2+ channels, using a potent combination of techniques, including patch clamp and calmodulin distributions.
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