Histamine stimulates glycogen breakdown and increases 45Ca2+ permeability in rat astrocytes in primary culture

Abstract

In astrocyte-enriched cultures from rat brain hemispheres prelabeled with [3H]glucose, histamine stimulates [3H]glycogen breakdown in a concentration-dependent manner, with an EC50 of 0.6 microM. This effect can be induced by activation of both H1 and H2 receptors independently. Thus, neither 1 microM promethazine, an H1 antagonist, or 100 microM metiamide, an H2 antagonist, inhibited the glycogenolytic response to histamine unless they were present together. In addition, the maximal effect of histamine (55% decrease in [3H]glycogen) was also elicited by 300 microM 2-thiazolylethylamine, an H1 agonist, and by 1 mM dimaprit, an H2 agonist. These agonist effects were inhibited by promethazine and metiamide, respectively, and were not additive, indicating that the same glycogen pool was affected. Histamine was more potent in eliciting glycogenolysis through H1 (EC50 of 0.4 microM in the presence of 100 microM metiamide) than through H2 (EC50 of 3.3 microM in the presence of 1 microM promethazine) receptors, as also shown previously for the H1-mediated phosphoinositide hydrolysis compared with the H2-mediated cAMP formation in the same cells. Both dibutyryl cyclic AMP and the Ca2+ ionophore A23187 could independently mimic the glycogenolytic effect of histamine, whereas the absence of extracellular Ca2+ abolished the H1 component of the response. Histamine also stimulated rapid transmembrane 45Ca2+ influx (maximum, 48% of basal at 15 sec) and efflux (maximum, 25% of basal at 1 min) in astrocytes by activation of H1 receptors. This histamine-increased 45Ca2+ entry was abolished by the nonspecific Ca2+ channel blocker lanthanum but not by the voltage-operated Ca2+ channel inhibitor nifedipine. The enhanced 45Ca2+ release was more a consequence of the histamine-increased Ca2+ permeability than intracellular Ca2+ mobilization, because it was largely diminished when Ca2+ entry was prevented and was little affected by pretreatment of the cells with 12-O-tetradecanoyl-phorbol-13-acetate. Thus, the histamine-induced glycogen breakdown in astrocytes may involve increases in cAMP formation and in intracellular Ca2+ levels, this latter resulting mainly from H1-mediated extracellular Ca2+ uptake.