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This Article Full Text Full Text (PDF) All Versions of this Article: 560/1/63    most recent jphysiol.2004.064063v2 jphysiol.2004.064063v1 Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Cuchillo-Ibáñez, I Articles by Trifaró, J.-M Search for Related Content PubMed PubMed Citation Articles by Cuchillo-Ibáñez, I Articles by Trifaró, J.-M

¹ Instituto Teófilo Hernando, Department de Farmacología y Terapeútica, Facultad de Medicina, Universidad Autónoma de Madrid, E-28029, Madrid, Spain
² Secretory Process Research Program, Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada, K1H 8M

Mitochondria play an important role in the homeostasis of intracellular Ca²⁺ and regulate its availability for exocytosis. Inhibitors of mitochondria Ca²⁺ uptake such as protonophore CCCP potentiate the secretory response to a depolarizing pulse of K⁺. Exposure of cells to agents that directly (cytochalasin D, latrunculin B) or indirectly (PMA) disrupt cortical F-actin networks also potentiate the secretory response to high K⁺. The effects of cytochalasin D and CCCP on secretion were additive whereas those of PMA and CCCP were not; this suggests different mechanisms for cytochalasin D and CCCP and a similar mechanism for PMA and CCCP. Mitochondria were the site of action of CCCP, because the potentiation of secretion by CCCP was observed even after depletion of Ca²⁺ from the endoplasmic reticulum. CCCP induced a small increase in the cytosolic Ca²⁺ concentration ([Ca²⁺]_c) that was not modified by the protein kinase C (PKC) inhibitor chelerythrine. Both CCCP and PMA induced cortical F-actin disassembly, an effect abolished by chelerythrine. In addition, rotenone and oligomycin A, two other mitochondrial inhibitors, also evoked cortical F-actin disassembly and potentiated secretion; again, these effects were blocked by chelerythrine. CCCP also enhanced the phosphorylation of PKC and myristoylated alanine-rich C kinase substance (MARCKS), and these were also inhibited by chelerythrine. The results suggest that the rapid sequestration of Ca²⁺ by mitochondria would protect the cell from an enhanced PKC activation and cortical F-actin disassembly, thereby limiting the magnitude of the secretory response.

(Received 9 March 2004; accepted after revision 2 May 2004; first published online 7 May 2004)
Corresponding author J.-M. Trifaró: Secretory Process Research Program, Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada K1H 8M5. Email: jtrifaro{at}uottawa.ca

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