Signal transduction via protein phosphorylation plays a critical role in learning and memory. In a prominent candidate mechanism for mammalian learning and memory, hippocampal long-term potentiation (LTP), a diverse set of protein kinases plays an important role. Thus, the cAMP-dependent protein kinase (PKA), calcium/phospholipid-dependent kinase (PKC), calcium/calmodulin-dependent protein kinase (CaMKII), and mitogen-activated protein kinase (MAP kinase) all are necessary for the induction of various phases of LTP. While great progress has been made in identifying the kinases involved in LTP, there are many gaps in our knowledge of how the protein kinases are regulated by NMDA receptor-dependent and independent processes during LTP. In addition, little is understood concerning the downstream targets of these kinases. To address this question, three specific aims are proposed:
Specific Aim 1, to investigate the regulation of phosphorylation of the Shal-type K+ channel Kv4.2 in LTP, Specific Aim 2, to investigate the biochemical mechanisms for the activation of MAP kinase during LTP and Specific Aim 3, to investigate the role of protein kinases in regulating CREB phosphorylation during LTP. These studies will provide insight into mechanisms involved in long-lasting changes in neuronal function in the mammalian CNS and should increase our understanding of the molecular basis of neuropsychiatric disorders.
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