This laboratory investigates the roles of protein phosphorylation and oxidation involved in synaptic transmission and plasticity. Modifications of protein by phosphorylation and oxidation are important mechanisms for the modulation of a plethora of cellular responses. Protein phosphorylation catalyzed by a variety of protein kinases and oxidation by many endogenously produced oxidants have been linked to the regulation of cellular processes as diverse as ion channels, cellular metabolism, synaptic plasticity, and growth and differentiation. Studies of these neural processes are essential to understanding the complex problem related to learning and memory. Our approach is to generate genetically modified mice by deletion or expression of a gene specifically expressed in the brain. These efforts have led us to generate a strain of mice devoid of a neural-specific protein, neurogranin (Ng). This protein is normally expressed at high levels in the neurons within cerebral cortex, hippocampus, and amygdala and has been implicated in the modulation of synaptic plasticity. Ng binds calmodulin (CaM) in an inverse Ca2+-sensitive manner; namely, its binding affinity for CaM decreases with increasing Ca2+ concentration. It is believed that at basal levels of Ca2+ all CaM is sequestered by Ng, whose cellular concentration is much higher than that of CaM. Upon synaptic stimulation, the influxed Ca2+ will displace Ng from the Ng/CaM complex to form Ca2+/CaM. The buffering of CaM by Ng serves as a mechanism to regulate neuronal free Ca2+ and Ca2+/CaM concentrations. Furthermore, Ng is readily phosphorylated by protein kinase C (PKC) and oxidized by nitric oxide (NO) and other oxidants. Both the phosphorylated and oxidized Ng exhibit lower affinities for CaM than the unmodified protein; thus, these modifications of Ng extend the availability of CaM even after the intracellular level of Ca2+ is reduced to basal levels. Synaptic responses triggering long-term potentiation (LTP) or long-term depression (LTD) depend on the amplitude of Ca2+ influx and the sensitivity of the transduction machinery to amplify the signal. Based on our previous finding that the autophosphorylation of Ca2+/CaM-dependent protein kinase II was enhanced by Ng, we speculate that other Ca2+- and Ca2+/CaM-regulated pathways are also upregulated by neurogranin. The multifarious effects of Ng could account for the positive impact of this protein on the behavior of mice. Investigation of the regulatory mechanism of synaptic transmission and plasticity by Ng will help us to design novel therapeutic approaches with the potential to improve memory in human and alleviate symptoms related to dementia.
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