The importance of calcium in the regulation of megakaryocyte function |
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Authors: | Christian Andrea Di Buduo Francesco Moccia Monica Battiston Luigi De Marco Mario Mazzucato Remigio Moratti Franco Tanzi Alessandra Balduini |
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Affiliation: | 1.Biotechnology Research Laboratories, Department of Molecular Medicine, IRCCS San Matteo Foundation, University of Pavia, Italy;2.Department of Biology and Biotechnology “Lazzaro Spallanzani”, University of Pavia, Italy;3.Centro di Riferimento Oncologico, Aviano, Italy;4.Scientific Direction, IRCCS San Matteo Foundation, Pavia, Italy;5.Department of Biomedical Engineering, Tufts University, Medford, MA, USA |
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Abstract: | Platelet release by megakaryocytes is regulated by a concert of environmental and autocrine factors. We previously showed that constitutively released adenosine diphosphate by human megakaryocytes leads to platelet production. Here we show that adenosine diphosphate elicits, in human megakaryocytes, an increase in cytosolic calcium concentration, followed by a plateau, which is lowered in the absence of extracellular calcium, suggesting the involvement of Store-Operated Calcium Entry. Indeed, we demonstrate that megakaryocytes express the major candidates to mediate Store-Operated Calcium Entry, stromal interaction molecule 1, Orai1 and canonical transient receptor potential 1, which are activated upon either pharmacological or physiological depletion of the intracellular calcium pool. This mechanism is inhibited by phospholipase C or inositol-3-phosphate receptor inhibitors and by a specific calcium entry blocker. Studies on megakaryocyte behavior, on extracellular matrix proteins that support proplatelet extension, show that calcium mobilization from intracellular stores activates signaling cascades that trigger megakaryocyte adhesion and proplatelet formation, and promotes extracellular calcium entry which is primarily involved in the regulation of the contractile force responsible for megakaryocyte motility. These findings provide the first evidence that both calcium mobilization from intracellular stores and extracellular calcium entry specifically regulate human megakaryocyte functions. |
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