BackgroundTraumatic brain injury (TBI) sets in motion cascades of biochemical changes that result in delayed cell death and altered neuronal architecture. Studies have demonstrated that inhibition of glycogen synthase kinase-3 (GSK-3) effectively reduces apoptosis following a number of stimuli. The Wnt family of proteins, and growth factors are two major factors that regulate GSK-3 activity. In the absence of stimuli, GSK-3 is constitutively active and is complexed with Axin, adenomatous polyposis coli (APC), and casein kinase Iα (CK1α) and phosphorylates ß-Catenin leading to its degradation. Binding of Wnt to Frizzled receptors causes the translocation of GSK-3 to the plasma membrane, where it phosphorylates and inactivates the Frizzled co-receptor lipoprotein-related protein 6 (LRP6). Furthermore, the translocation of GSK-3 reduces ß-Catenin phosphorylation and degradation, leading to ß-Catenin accumulation and gene expression. Growth factors activate Akt, which in turn inhibits GSK-3 activity by direct phosphorylation, leading to a reduction in apoptosis.Methodology/Principal FindingsUsing a rodent model, we found that TBI caused a rapid, but transient, increase in LRP6 phosphorylation that is followed by a modest decrease in ß-Catenin phosphorylation. Phospho-GSK-3β immunoreactivity was found to increase three days post injury, a time point at which increased Akt activity following TBI has been observed. Lithium influences several neurochemical cascades, including inhibiting GSK-3. When the efficacy of daily lithium was assessed, reduced hippocampal neuronal cell loss and learning and memory improvements were observed. These influences were partially mimicked by administration of the GSK-3-selective inhibitor SB-216763, as this drug resulted in improved motor function, but only a modest improvement in memory retention and no overt neuroprotection.Conclusion/SignificanceTaken together, our findings suggest that selective inhibition of GSK-3 may offer partial cognitive improvement. As a broad spectrum inhibitor of GSK-3, lithium offers neuroprotection and robust cognitive improvement, supporting its clinical testing as a treatment for TBI.

An analytical model of V-type H+-translocating ATPase (V-ATPase) was developed based on an approximation to the mechanochemical model of Grabe et al. (Biophys. J., pp. 2798-2813, vol. 78, 2000). Grabe's work utilizes structural information and physiological assumptions to construct a detailed mechanochemical model of the V-ATPase. Due to the complexity of their model, it does not give a readily usable mathematical expression for the V-ATPase current. Based on their analysis of the structure of the proton pump, we develop a two-compartment model of the V-ATPase, which contains a membrane "half-channel" for proton translocation separated by a hydrophilic strip and a hydrophobic wall from the cytoplasm. Using the Langevin equation to describe proton transport across the membrane, we simplify the model based on their assumptions on the molecular structure of the pump and arrive at a general form of solution to the proton pump flux driven by ATP hydrolysis based on assumptions on the physiological properties of the strip and the wall, as well as the two fluid compartments. In this process of simplification, we explicitly relate V-ATPase structure, stoichiometry, pump efficiency, and ATP hydrolysis energy to the active pump current. The simplified model is used to provide model-generated approximations to measured data from a variety of laboratories. In addition, it provides a very compact characterization of V-ATPase, which can be used as a proton extruder in a variety of different cell membranes, as well as in the membranes of intracellular organelles. Index Terms-Electrophysiology, mechanochemstry, molecular motors, proton extrusion

No abstract

No abstract