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Vol. 20, Issue 16, 3638-3645, August 15, 2009

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Human Golgi Antiapoptotic Protein Modulates Intracellular Calcium Fluxes

Fabrizio de Mattia^*, Caroline Gubser, Michiel M.T. van Dommelen^*, Henk-Jan Visch, Felix Distelmaier, Antonio Postigo, Tomas Luyten, Jan B. Parys, Humbert de Smedt, Geoffey L. Smith, Peter H.G.M. Willems, and Frank J.M. van Kuppeveld^*

Departments of *Medical Microbiology and Biochemistry, Radboud University Nijmegen Medical Centre, Nijmegen Centre for Molecular Life Sciences, 6500 HB Nijmegen, The Netherlands; Department of Virology, Faculty of Medicine, Imperial College London, St Mary's Campus, London W2 1PG, United Kingdom; and Laboratory of Molecular Signalling, Division of Physiology, Department of Cell Biology, Catholic University Leuven, B-3000 Leuven, Belgium

Submitted May 11, 2009; Accepted June 16, 2009
Monitoring Editor: John York

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 Ca²⁺ homeostasis play an important role in determining cell sensitivity to apoptosis, we investigated if GAAP affected Ca²⁺ signaling. Overexpression of human (h)-GAAP suppressed staurosporine-induced, capacitative Ca²⁺ influx from the extracellular space. In addition, it reduced histamine-induced Ca²⁺ release from intracellular stores through inositol trisphosphate receptors. h-GAAP not only decreased the magnitude of the histamine-induced Ca²⁺ fluxes from stores to cytosol and mitochondrial matrices, but it also reduced the induction and frequency of oscillatory changes in cytosolic Ca²⁺. Overexpression of h-GAAP lowered the Ca²⁺ content of the intracellular stores and decreased the efficacy of IP₃, 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 Ca²⁺ fluxes induced by both physiological and apoptotic stimuli.

Address correspondence to: Peter H.G.M. Willems (p.willems{at}ncmls.ru.nl) or Frank J.M. van Kuppeveld (f.vankuppeveld{at}ncmls.ru.nl).

Abbreviations used: ATP, adenosine triphosphate; ER, endoplasmic reticulum; GAAP, Golgi antiapoptotic protein; HA, hemagglutinin; IP₃, inositol-1,4,5-trisphosphate; IP₃R, IP₃ receptor; PMCA, plasma membrane Ca²⁺-ATPase; SERCA, sarcoendoplasmic reticulum Ca²⁺-ATPase; siRNA, small interfering RNA; TG, thapsigargin.