Protein Phosphatase Inhibitor-1 and Cdk5: of Molecules and Memory

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Title: Protein Phosphatase Inhibitor-1 and Cdk5: of Molecules and Memory
Author: Nguyen, Baochan
Abstract: Protein phosphatase inhibitor -1 and cyclin -dependent kinase 5 (Cdk5 ) have been independently implicated in synaptic plasticity , learning , and memory . We began our studies with the identification , confirmation , and characterization of a novel Cdk5 -dependent phosphorylation site (Ser6 ) on inhibitor -1 . In the striatum , basal in vivo phosphorylation and dephosphorylation of Ser6 were mediated by Cdk5 and protein phosphatases 2A (PP -2A ) and 1 (PP -1 ) , respectively . Additionally , protein phosphatase 2B (PP -2B ) contributed to dephosphorylation under conditions of high Ca2+ . Functionally , Cdk5 -dependent phosphorylation of inhibitor -1 intramolecularly impaired dephosphorylation and deactivation of the protein , placing the activities of Cdk5 and protein kinase A (PKA ) in synergism in the negative regulation of PP -1 . These studies uncovered a potential new regulatory mechanism for Cdk5 . Investigation revealed that depolarization differentially regulates the Cdk5 -dependent sites of inhibitor -1 and its homologue dopamine - and cAMP -regulated phosphoprotein (DARPP -32 ) in a cofactor - and N -methyl -D -aspartate (NMDA ) receptor -independent manner . Effects on DARPP -32 were Ca2+ -mediated and PP -2A -dependent , while effects on inhibitor -1 were nonselectively cation -mediated and either partially PP -2B -dependent or independent of the major serine /threonine phosphatases , depending on the site . Given the uncertain role of inhibitor -1 in learning and memory , we next focused on identifying behaviors and substrates impacted by inhibitor -1 function . Mice constitutively lacking inhibitor -1 displayed enhanced neurogenesis and mildly impaired habituation , but normal contextual fear and novelty learning . Furthermore , levels of hippocampal inhibitor -1 were increased by voluntary wheel running , a stimulus for neurogenesis . Thus , inhibitor -1 may function in an anti -neurogenic mechanism and be more important in the direct or indirect modulation of dopamine -dependent behaviors than in the mnemonic functions of the hippocampus . Using a whole -cell patch clamp approach , we also attempted to identify electrical properties of dentate granule cells that might be affected by Cdk5 -dependent phosphorylation of inhibitor -1 . Most promising among the results was a reduction in the ability of granule cells lacking inhibitor -1 to faithfully respond to high -frequency trains of stimuli . Granule cell excitability was also increased by pharmacological inhibition of Cdk5 with roscovitine . Finally , in a related study , we helped firmly establish a role for Cdk5 in hippocampal synaptic plasticity by demonstrating that conditional loss of Cdk5 enhances NMDA receptor -mediated currents , particularly of the NR2B type .
URI: http : / /hdl .handle .net /2152 .5 /409
Date: 2007-06-12

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Protein Phosphatase Inhibitor-1 and Cdk5: of Molecules and Memory. Graduate School of Biomedical Sciences. Available electronically from http : / /hdl .handle .net /2152 .5 /409 .

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