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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2002;22:179.)
© 2002 American Heart Association, Inc.

Thrombosis

Cyclic AMP Raises Intracellular Ca²⁺ in Human Megakaryocytes Independent of Protein Kinase A

Els den Dekker; Johan W.M. Heemskerk; Gertie Gorter; Hans van der Vuurst; José Donath; Christine Kroner; Katsuhiko Mikoshiba; Jan-Willem N. Akkerman

From the Thrombosis and Haemostasis Laboratory (E.d.D., G.G., H.v.d.V., J.D., C.K., J.-W.N.A.), Department of Haematology, University Medical Center Utrecht and Institute for Biomembranes, Utrecht University, Utrecht, and the Department of Biochemistry and Human Biology (J.W.M.H.), Maastricht University, Maastricht, The Netherlands, and the Department of Molecular Neurobiology (K.M.), Institute of Medical Science, Tokyo University, Tokyo, Japan.

Correspondence to Els den Dekker, Thrombosis and Haemostasis Laboratory, Department of Haematology, University Medical Center Utrecht, PO Box 85500, 3508 GA Utrecht, The Netherlands. E-mail e.dendekker{at}lab.azu.nl

The immature megakaryoblastic cell line MEG-01 responds to iloprost with an increase in cytosolic Ca²⁺ and cAMP. The Ca²⁺ response is almost absent in CHRF-288-11 cells, but cAMP formation is preserved in this more mature megakaryoblastic cell line. Also, in human hematopoietic stem cells, iloprost induces a Ca²⁺ response and cAMP formation. The Ca²⁺ response is downregulated during megakaryocytopoiesis, but cAMP formation remains unchanged. The Ca²⁺ increase may be caused by cAMP-mediated inhibition of Ca²⁺ sequestration, because it is (1) independent of Ca²⁺ entry; (2) mimicked by forskolin, an activator of adenylyl cyclase, and isobutylmethylxanthine, an inhibitor of phosphodiesterases; and (3) preserved in the presence of inhibitors of protein kinase A and inositol-1,4,5-triphosphate receptors. The small GTPase Rap1 has been implicated in the control of Ca²⁺ sequestration. Indeed, Rap1 activation parallels the iloprost- and forskolin-induced Ca²⁺ increase and is unaffected by the calcium chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N',-tetraacetic acid-AM. These findings reveal a novel mechanism for elevating cytosolic Ca²⁺ by cAMP, possibly via GTP-Rap1.

Key Words: calcium • cAMP • stem cells • megakaryocytes • Rap1

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