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.
de Mattia
Fabrizio
F
Department of Medical Microbiology, Radboud University Nijmegen Medical Centre, The Netherlands.
Gubser
Caroline
C
van Dommelen
Michiel M T
MM
Visch
Henk-Jan
HJ
Distelmaier
Felix
F
Postigo
Antonio
A
Luyten
Tomas
T
Parys
Jan B
JB
de Smedt
Humbert
H
Smith
Geoffey L
GL
Willems
Peter H G M
PH
van Kuppeveld
Frank J M
FJ
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000502:physiology*; D006056:Golgi Apparatus / Q000378:metabolism; D006632:Histamine / Q000378:metabolism; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism
D053496:Inositol 1,4,5-Trisphosphate Receptors; D008565:Membrane Proteins; D034741:RNA, Small Interfering; C518281:TMBIM4 protein, human; D006632:Histamine; D015544:Inositol 1,4,5-Trisphosphate; D002118:Calcium