EFFECT OF SIGNAL-TRANSDUCTION PATHWAYS ON THE ACTION OF THAPSIGARGIN ON RAT MAST-CELLS - CROSSTALKS BETWEEN CELLULAR SIGNALING AND CYTOSOLIC PH

Thapsigargin elicits histamine release on rat mast cells, and this effect is increased if cells are pretreated with thapsigargin before the addition of external calcium. Okadaic acid does not modify the response of mast cells to thapsigargin, while sodium fluoride or the phorbol esther 12-O-tetradecanoylphorbol-13-acetate (TPA) increases several fold the sensitivity of cells to thapsigargin. On the other hand, pertussis and cholera toxins inhibit the response to thapsigargin. Thapsigargin increases the activity of the Na+-H+ exchanger, this effect being blocked by fluoride and not modified by TPA. The metals cadmium and lanthanum completely block the effect of TPA or thapsigargin on the Na+-H+ exchanger. The influx of Ca-45 in rat mast cells is not modified by thapsigargin, but if cells are treated with thapsigargin before the addition of calcium, the influx is markedly increased in the first 2 min before returning to normal. Our results indicate that exocytosis is modulated by crosstalks between intracellular calcium, cytosolic pH and external calcium.