Modulation of central nervous system metabolism by macromolecules: effects of albumin and histones on glucose oxidation by synaptosomes.

Abstract

Since increasing evidence suggests that several proteins play a significant role in the regulation of glucose oxidation in the central nervous system, a series of experiments was designed to determine the specific proteins involved and to delineate their possible mode of action. In these studies, the rate of substrate oxidation by isolated synaptosomes in vitro was determined by measuring the production of [14C]carbon dioxide from labeled compounds in the presence and absence of the added protein. In the initial experiments, an examination of a broad selection of pure proteins revealed that only albumin (bovine serum albumin [BSA]) or histones (at concentrations of 100 micrograms/mL or less) exhibited an inhibitory effect of greater than 60% on the rate of glucose oxidation. Furthermore, isolated cell fractions P1 (nuclei and cellular debris), P2 (mitochondria, synaptosomes, and myelin), and other membrane proteins had little or no effect on the rate of [14C]carbon dioxide production from [6(14)C]glucose. When either BSA or histones were treated with trypsin, the inhibitory effects were eliminated. To determine whether these effects were related to changes in substrate transport, we measured the rate of glucose uptake by synaptosomes using [6(14)C]glucose, [1,2-3H]2-deoxyglucose, and [3H]3-O-methylglucose in the presence of 5% serum protein. These experiments revealed that the rate of glucose transport was not affected by serum proteins. Collectively, these results indicate that albumin and histones attenuate the rate of glucose oxidation by synaptosomes. The results also support the conclusion that the intact protein molecule is required for this inhibition, since treatment with trypsin abolished this effect. It can also be concluded that this effect is not at the site of transport and that the protein(s) are acting either directly at intercellular site(s) or indirectly via specific messengers.