Regulation of Protein Phosphatase Inhibitor-1 by Cdk5

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DESCRIPTION (provided by applicant): While learning and memory have mystified people for centuries, a cellular model for these processes eluded scientists until the discovery of LTP and LTD in the 1970s. Three decades later a general biochemical cascade involving calcium/calmodulin-dependent kinase II (CaMKII), protein phosphatase 1 (PP-1), and inhibitor-1 has gained widespread acceptance, although many details remain obscure. This proposal will employ biochemical and neuropharmacological techniques to characterize a novel phosphorylation event on inhibitor-1 by cyclin-dependent kinase 5 (Cdk5) and its implications for synaptic plasticity. The kinetics of this phosphorylation reaction and its effect upon inhibitor-1 activation, deactivation, and inhibitory activity against PP-1 will be assessed. Hippocampal slices will then be used to characterize this event in vivo, in terms of basal levels of phosphorylation, as well as modulation by different signaling pathways and possible effects on downstream PP-1 targets. Finally, the phosphatase(s) responsible for dephosphorylation of this site will be determined by both in vitro and in vivo methods.