Voltage-gated Ca2+ channels (VGCCs) are transmembrane proteins, which allow Ca2+ entry upon activation. In addition to their electrogenic role, VGCCs provide a pivotal link between membrane depolarization and a wide range of non-electrical activities. Ca2+ influx through different types of VGCCs can activate/regulate distinct cellular signaling cascades. VGCCs are also targets for modulation by a variety of second messengers. Phosphorylation and dephosphorylation are important means of rapid regulation of the Ca2+ channel activity. Emerging evidence shows that formation of macromolecular signaling complexes is one the of the mechanisms for the specificity of the Ca2+ channel action as well as rapid regulation of the channel activity by protein kinases and/or phosphatases. The long term goal of this project is to understand the unique role of Ca2+ channel partner proteins in neuronal signaling. In this application, we will focus on three novel Ca2+ channel partner proteins, identified via yeast two-hybrid screening, for their roles in formation of a PKC signaling complex as well as in targeting mRNAs to dendrites and/or axons for activity-dependent localized protein synthesis. Several different hypotheses will be tested, using the combined approaches of molecular and cell biology, biochemistry, fluorescent imaging and electrophysiology. We will address: (1) Physiological factors, such as phosphorylation by protein kinases, regulate formation of the PKCe-ENH-N-type Ca2+ channel complex. (2) Novel Ca2+ binding domains exist, responsible for differential regulation of the interactions between PKCe-ENH and ENH-N-type Ca2+ channels. (3) The functional PKC signaling complex includes a protein phosphatase, PP2ca, which binds directly to the C-terminus of Ca2+ channels. (4) A novel channel partner protein, PQ-46, which is an RNA binding protein and binds to N- and P/Q-type Ca2+ channels, may be involved in activity dependent targeting of mRNAs to dendrites and/or axons. The results will shed light on how the cellular signaling network, established via protein-protein interactions, achieves its specificity. Results of this study will provide molecular mechanisms of signal transduction in the brain and will help understand normal neurological functions, such as learning and memory, and provide reasons for neurological disorders, such as Alzheimer's disease. ? ?

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Neurotransporters, Receptors, and Calcium Signaling Study Section (NTRC)
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Silberberg, Shai D
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Thomas Jefferson University
Schools of Medicine
United States
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