HISTAMINE H-1 RECEPTOR ACTIVATION STIMULATES [H-3] GABA RELEASE FROM HUMAN ASTROCYTOMA U373 MG CELLS

In U373 MG cells, a line derived from a human astrocytoma, histamine s timulated the release of [H-3]gamma-aminobutyric acid ([H-3]GABA) in a concentration-dependent manner (286 +/- 23% of basal release at 1 mM histamine). Neither Ca2+ removal nor Cd2+ (100 mu M) affected [H-3]GAB A release evoked by 100 mu M histamine but the response was significan tly reduced by 10 mu M U-73122 ({1-[6-((17 trien-17-yl)-amino)-hexyl]- 1H-pyrrole-2,5-dione}), an inhibitor of phospholipase C activation (79 +/- 8% inhibition) and by 10 mu M dimethylbenzamil, a selective block er of plasma membrane Na+/Ca2+ exchange (58 +/- 6% inhibition). In [H- 3]inositol-labelled cells histamine stimulated [H-3]inositol phosphate accumulation (EC(50), 17 +/- 2 mu M; maximum effect, 203 +/- 4% of ba sal). Histamine-evoked Ca2+ mobilisation yielded an EC(50) of 12 +/- 2 mu M and maximum Delta[Ca2+](i) of 337 +/- 23 nM. Thapsigargin (1 nM) increased [Ca2+](i) (Delta[Ca2+](i) 164 +/- 12 nM) and prevented any further increase by histamine (100 mu M). The effects of histamine on [H-3]GABA release, [H-3]inositol phosphate accumulation and Ca2+ mobil isation were blocked by the selective histamine H-1 receptor antagonis t mepyramine. Taken together, these results indicate that histamine st imulates [H-3]GABA release by increasing [Ca2+](i). The mechanism of r elease may be related to changes in transmembranal Na+ gradients and r eversal of GABA carrier transport due to stimulation of plasma membran e Na+/Ca2+ exchange.