Human Golgi antiapoptotic protein modulates intracellular calcium fluxes

Golgi antiapoptotic protein (GAAP) is a novel regulator of cell death that is highly conserved in eukaryotes and present in some poxviruses, but its molecular mechanism is unknown. Given that alterations in intracellular CA(2+) homeostasis play an important role in determining cell sensitivity to Apoptosis, we investigated if GAAP affected CA(2+) signaling. Overexpression of human (h)-GAAP suppressed staurosporine-induced, capacitative CA(2+) influx from the extracellular space. In addition, it reduced histamine-induced CA(2+) release from intracellular stores through inositol trisphosphate receptors. h-GAAP not only decreased the magnitude of the histamine-induced CA(2+) fluxes from stores to cytosol and mitochondrial matrices, but it also reduced the induction and frequency of oscillatory changes in cytosolic CA(2+). Overexpression of h-GAAP lowered the CA(2+) content of the intracellular stores and decreased the efficacy of IP(3), providing possible explanations for the observed results. Opposite effects were obtained when h-GAAP was knocked down by siRNA. Thus, our data demonstrate that h-GAAP modulates intracellular CA(2+) fluxes induced by both physiological and apoptotic stimuli.