Cyclic AMP and calcium interplay as second messengers in melatonin-dependent regulation of Plasmodium falciparum cell cycle

J Cell Biol. 2005 Aug 15;170(4):551-7. doi: 10.1083/jcb.200505117.


The host hormone melatonin increases cytoplasmic Ca(2+) concentration and synchronizes Plasmodium cell cycle (Hotta, C.T., M.L. Gazarini, F.H. Beraldo, F.P. Varotti, C. Lopes, R.P. Markus, T. Pozzan, and C.R. Garcia. 2000. Nat. Cell Biol. 2:466-468). Here we show that in Plasmodium falciparum melatonin induces an increase in cyclic AMP (cAMP) levels and cAMP-dependent protein kinase (PKA) activity (40 and 50%, respectively). When red blood cells infected with P. falciparum are treated with cAMP analogue adenosine 3',5'-cyclic monophosphate N6-benzoyl/PKA activator (6-Bz-cAMP) there is an alteration of the parasite cell cycle. This effect appears to depend on activation of PKA (abolished by the PKA inhibitors adenosine 3',5'-cyclic monophosphorothioate/8 Bromo Rp isomer, PKI [cell permeable peptide], and H89). An unexpected cross talk was found to exist between the cAMP and the Ca(2+)-dependent signaling pathways. The increases in cAMP by melatonin are inhibited by blocker of phospholipase C U73122, and addition of 6-Bz-cAMP increases cytosolic Ca(2+) concentration, through PKA activation. These findings suggest that in Plasmodium a highly complex interplay exists between the Ca(2+) and cAMP signaling pathways, but also that the control of the parasite cell cycle by melatonin requires the activation of both second messenger controlled pathways.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium / metabolism*
  • Cell Cycle / drug effects*
  • Cyclic AMP / metabolism*
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Enzyme Inhibitors / pharmacology
  • Melatonin / pharmacology*
  • Microscopy, Confocal
  • Models, Biological
  • Parasites / cytology
  • Parasites / drug effects
  • Parasites / enzymology
  • Plasmodium falciparum / cytology*
  • Plasmodium falciparum / drug effects*
  • Plasmodium falciparum / enzymology
  • Second Messenger Systems*
  • Signal Transduction / drug effects
  • Type C Phospholipases / antagonists & inhibitors


  • Enzyme Inhibitors
  • Cyclic AMP
  • Cyclic AMP-Dependent Protein Kinases
  • Type C Phospholipases
  • Melatonin
  • Calcium