Intracellular kinetics of high energy phosphates (HEP) is of fundamental importance in cellular biochemical physiology. In mammalian brain, intracellular HEP transport from the production site (mitochondria) to the consumption site (plasma membrane) is dependent on passive diffusion of HEP through the cytosol. Diffusivity of a substrate in a solution correlates inversely to the viscosity of the solution. The maturational process of mammalian brain involves dramatic changes in the cytosolic amino acid profile. Since the viscosity of a solution is a function of the diffusion coefficients of solutes and their concentrations, changes in the cytosolic amino acid composition should result in significant alteration in cytosol viscosity and, hence, HEP diffusivity. Nevertheless, to date, little is known regarding the effect of maturational changes in cytosol composition on the diffusivity of HEP or intracellular HEP kinetics. Using in vivo nuclear magnetic resonance (NMR) diffusion spectroscopy and saturation transfer experiments, the investigators have recently demonstrated that diffusivity of HEP in rat brain indeed exhibits significant changes during the postnatal maturational period. This proposal aims to further investigate HEP diffusivity and kinetics in vivo and in vitro as a function of maturation. Studies are designed to provide a correlation between maturational changes in the cytosolic amino acid profile and HEP diffusivity, and to elucidate the maturational changes in HEP kinetics. A mathematical model of HEP diffusion is presented. The role of N-acetyl-aspartate, an amino acid present in high concentrations in adult of N-acetyl-aspartate, an amino acid present in high concentrations in adult brain and the function of which remains elusive, is expected to be clarified.
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