Cyclic AMP Raises Intracellular Ca 2+ 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
2002 Arteriosclerosis, Thrombosis and Vascular Biology  
The immature megakaryoblastic cell line MEG-01 responds to iloprost with an increase in cytosolic Ca 2ϩ and cAMP. The Ca 2ϩ 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 Ca 2ϩ response and cAMP formation. The Ca 2ϩ response is downregulated during megakaryocytopoiesis, but cAMP formation remains unchanged. The Ca 2ϩ increase may be caused by cAMP-mediated
more » ... inhibition of Ca 2ϩ sequestration, because it is (1) independent of Ca 2ϩ 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 Ca 2ϩ sequestration. Indeed, Rap1 activation parallels the iloprost-and forskolin-induced Ca 2ϩ increase and is unaffected by the calcium chelator 1,2-bis(2aminophenoxy)ethane-N,N,NЈ,NЈ,-tetraacetic acid-AM. These findings reveal a novel mechanism for elevating cytosolic Ca 2ϩ by cAMP, possibly via GTP-Rap1. (Arterioscler Thromb Vasc Biol. 2002;22:179-186.)
doi:10.1161/hq0102.101515 pmid:11788480 fatcat:krpgeozcoff2nmdmah55x7ll54