{"id":{"repo_id":"utswmed","oai_identifier":"oai:utswmed-ir.tdl.org:2152.5/409"},"canonical_url":"https://search.dev.ndltd.org/etd/utswmed/oai:utswmed-ir.tdl.org:2152.5/409","repository":{"repo_id":"utswmed","name":"University of Texas Southwestern Medical Center","base_url":"https://utswmed-ir.tdl.org/server/oai/request"},"display":{"title":"Protein Phosphatase Inhibitor-1 and Cdk5: Of Molecules and Memory","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.","abstract_html":"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.","abstract_has_math":false,"creators":["Nguyen, Baochan"],"institution":null,"degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":["Bibb, James A."],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2010,"date_issued":"2010-07-12T17:58:01Z","date_published":"2010-07-12T17:58:01Z","updated_at":"2026-07-24T05:52:06Z","subjects":["Signal Transduction","Cyclin-Dependent Kinase 5","Protein Processing, Post-Translational"],"languages":["en"],"rights":[],"rights_urls":[],"identifier_entries":[{"key":"dc:identifier","label":"Identifier","values":["755068856"],"render_values":[{"text":"755068856","href":null,"code":true}]}]},"links":{"outbound_url":"https://hdl.handle.net/2152.5/409","outbound_label":"Handle","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Bibb, James A."]},{"key":"dc:creator","label":"Author","values":["Nguyen, Baochan"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2010-07-12T17:58:01Z","2007-06-12"]},{"key":"dc:type","label":"Dc Type","values":["Thesis","Text","dissertation"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Signal Transduction","Cyclin-Dependent Kinase 5","Protein Processing, Post-Translational"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["en"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["https://hdl.handle.net/2152.5/409","755068856"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["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."]},{"key":"dc:format","label":"Dc Format","values":["Electronic","application/pdf","born digital"]},{"key":"dc:title","label":"Title","values":["Protein Phosphatase Inhibitor-1 and Cdk5: Of Molecules and Memory"]}]}],"canonical_facts":{"dc:contributor":["Bibb, James A."],"dc:creator":["Nguyen, Baochan"],"dc:date":["2010-07-12T17:58:01Z","2007-06-12"],"dc:description":["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."],"dc:format":["Electronic","application/pdf","born digital"],"dc:identifier":["https://hdl.handle.net/2152.5/409","755068856"],"dc:language":["en"],"dc:subject":["Signal Transduction","Cyclin-Dependent Kinase 5","Protein Processing, Post-Translational"],"dc:title":["Protein Phosphatase Inhibitor-1 and Cdk5: Of Molecules and Memory"],"dc:type":["Thesis","Text","dissertation"]},"updated_at":"2026-07-24T05:52:06Z"}