ENDOTHELIN-1 REGULATES GLUCOSE-UTILIZATION IN CULTURED ASTROCYTES BY CONTROLLING INTERCELLULAR COMMUNICATION THROUGH GAP-JUNCTIONS

The role played by endothelin-1 and intercellular communication mediat ed by gap junctions in the regulation of glucose disposal by astrocyte s has been studied in primary culture. Endothelin-1 increased glucose uptake by astrocytes as did one of its putative messenger arachidonic acid and the non-physiological gap junction uncoupler alpha-glycyrrhet inic acid (ACTA). None of these agents increased glucose uptake by C6 glioma cells, a cell line in which gap junction proteins are poorly ex pressed. In confluent astrocytes, the inhibition of gap junction perme ability caused by AGA doubled the activity of the pentose phosphate sh unt with minimal changes in the activity of the pyruvate dehydrogenase -catalyzed reaction and that of the tricarboxylic acid cycle. By contr ast, these effects were not observed in dissociated astrocytes in whic h intercellular communication is lacking. The scraped loading dye tran sfer technique was modified to follow the passage of glucose and its m etabolites through astrocyte gap junctions. The diffusion of glucose, the phosphorylated derivative glucose-6-phosphate, the phosphorylisabl e but not metabolisable derivative ortho-methyl-glucose, and the anaer obic glycolytic product L-lactate was much higher in astrocytes than i n C6 glioma cells and was inhibited by the inhibition of gap junction permeability caused by endothelin-1, arachidonic acid, octanol, or AGA . It is concluded that gap junction permeability may regulate brain me tabolism by controlling the uptake, utilization, and intercellular dis tribution of glucose and its metabolites in astrocytes. (C) 1996 Wiley -Liss, Inc.