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Published 15 August 2005. doi:10.1083/jcb.200505117
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 170, Number 4, 551-557
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Article

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

Flávio H. Beraldo1, Fabiana M. Almeida2, Aline M. da Silva2, and Célia R.S. Garcia3

1 Departamento de Parasitologia, Instituto de Ciências Biomédicas
2 Departamento de Bioquímica, Instituto de Química
3 Departamento de Fisiologia, Instituto de Biociências, Universidade de São Paulo, 05508-900, São Paulo, SP, Brasil

Correspondence to Célia R.S. Garcia: cgarcia{at}usp.br

The host hormone melatonin increases cytoplasmic Ca2+ 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 Ca2+-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 Ca2+ concentration, through PKA activation.

These findings suggest that in Plasmodium a highly complex interplay exists between the Ca2+ 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.

Abbreviations used in this paper: 6-Bz-cAMP, adenosine 3',5'-cyclic monophosphate N6-benzoyl/PKA activator; 8-BrcAMP-RP isomer, adenosine 3',5'-cyclic monophosphorothioate/8 Bromo Rp isomer; H89 and PKI, PKA inhibitors; IBMX, 3-isobutyl-1-methylxanthine; PKA, cAMP-dependent protein kinase; RBC, red blood cell.


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