This project focuses on the functions of protein kinases and protein phosphatases in transducing extracellular signals initiated by hormones, neurotransmitters, growth factors, and antigens. Covalent modification of proteins by phosphorylation/dephosphorylation plays a central role in mediating many cellular events resulting from ligand-receptor interaction and generation of a variety of second messengers. Several protein kinases, especially the Ca2+/phospholipid/diacylglycerol- stimulated protein kinase C family, and phosphatases have been prepared from rat brain for the identification of protein substrates modified by these enzymes. Several novel proteins have been isolated by ion-exchange and reverse phase chromatography and their partial amino acid sequences determined. The effects of phospholipids and Ca2+-binding proteins, calmodulin, and S-100 protein on the phosphorylation/dephosphorylation of these proteins are being investigated. In addition, modification of the protein kinase C substrate, neurogranin, by oxidizing agents such as hydrogen peroxide and nitric oxide has been shown to influence the kinase-catalyzed phosphorylation. Molecular cloning of the cDNAs of these novel protein kinase C substrates is in progress. The genomic structures of the CNS-specific protein kinase ~ isozyme and its substrate, neurogranin, have been elucidated. The mechanisms controlling the tissue-specific and developmental stage-regulated expression of these two genes are currently being investigated.

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Huang, Freesia L; Huang, Kuo-Ping; Boucheron, Catherine (2007) Long-term enrichment enhances the cognitive behavior of the aging neurogranin null mice without affecting their hippocampal LTP. Learn Mem 14:512-9
Huang, Kuo-Ping; Huang, Freesia L; Shetty, Pavan K et al. (2007) Modification of protein by disulfide S-monoxide and disulfide S-dioxide: distinctive effects on PKC. Biochemistry 46:1961-71
Huang, Freesia L; Huang, Kuo-Ping; Wu, Junfang et al. (2006) Environmental enrichment enhances neurogranin expression and hippocampal learning and memory but fails to rescue the impairments of neurogranin null mutant mice. J Neurosci 26:6230-7
Huang, Kuo-Ping; Huang, Freesia L; Jager, Tino et al. (2004) Neurogranin/RC3 enhances long-term potentiation and learning by promoting calcium-mediated signaling. J Neurosci 24:10660-9
Wu, Junfang; Huang, Kuo-Ping; Huang, Freesia L (2003) Participation of NMDA-mediated phosphorylation and oxidation of neurogranin in the regulation of Ca2+- and Ca2+/calmodulin-dependent neuronal signaling in the hippocampus. J Neurochem 86:1524-33
Wu, Junfang; Li, Junfa; Huang, Kuo-Ping et al. (2002) Attenuation of protein kinase C and cAMP-dependent protein kinase signal transduction in the neurogranin knockout mouse. J Biol Chem 277:19498-505
Watson, J B; Khorasani, H; Persson, A et al. (2002) Age-related deficits in long-term potentiation are insensitive to hydrogen peroxide: coincidence with enhanced autophosphorylation of Ca2+/calmodulin-dependent protein kinase II. J Neurosci Res 70:298-308
Miyakawa, T; Yared, E; Pak, J H et al. (2001) Neurogranin null mutant mice display performance deficits on spatial learning tasks with anxiety related components. Hippocampus 11:763-75
Li, J; Huang, F L; Huang, K P (2001) Glutathiolation of proteins by glutathione disulfide S-oxide derived from S-nitrosoglutathione. Modifications of rat brain neurogranin/RC3 and neuromodulin/GAP-43. J Biol Chem 276:3098-105
Xiao, D M; Pak, J H; Wang, X et al. (2000) Phosphorylation of HMG-I by protein kinase C attenuates its binding affinity to the promoter regions of protein kinase C gamma and neurogranin/RC3 genes. J Neurochem 74:392-9

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