The importance of calcium in the regulation of megakaryocyte function.
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.
alessandra.balduini@unipv.it.
Christian Andrea
CA
Di Buduo
Francesco
F
Moccia
Monica
M
Battiston
Luigi
L
De Marco
Mario
M
Mazzucato
Remigio
R
Moratti
Franco
F
Tanzi
Alessandra
A
Balduini
D000244:Adenosine Diphosphate / Q000378:metabolism / Q000494:pharmacology; D000328:Adult; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects; D002448:Cell Adhesion; D002465:Cell Movement; D002478:Cells, Cultured; D024042:Collagen Type I / Q000378:metabolism; D005110:Extracellular Space / Q000378:metabolism; D005260:Female; D006801:Humans; D008533:Megakaryocytes / Q000187:drug effects / Q000378:metabolism*; D011247:Pregnancy; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034061:Thrombopoiesis / Q000187:drug effects / Q000502:physiology
D024042:Collagen Type I; D012333:RNA, Messenger; D000244:Adenosine Diphosphate; D002118:Calcium