title: The central role of cAMP in regulating Plasmodium falciparum merozoite invasion of human erythrocytes.
abstract: All pathogenesis and death associated with Plasmodium falciparum malaria is due to parasite-infected erythrocytes. Invasion of erythrocytes by P. falciparum merozoites requires specific interactions between host receptors and parasite ligands that are localized in apical organelles called micronemes. Here, we identify cAMP as a key regulator that triggers the timely secretion of microneme proteins enabling receptor-engagement and invasion. We demonstrate that exposure of merozoites to a low K+ environment, typical of blood plasma, activates a bicarbonate-sensitive cytoplasmic adenylyl cyclase to raise cytosolic cAMP levels and activate protein kinase A, which regulates microneme secretion. We also show that cAMP regulates merozoite cytosolic Ca2+ levels via induction of an Epac pathway and demonstrate that increases in both cAMP and Ca2+ are essential to trigger microneme secretion. Our identification of the different elements in cAMP-dependent signaling pathways that regulate microneme secretion during invasion provides novel targets to inhibit blood stage parasite growth and prevent malaria.
authors.affiliation: Malaria Group, International Centre for Genetic Engineering and Biotechnology (ICGEB), New Delhi, India.
authors.forename: Amrita
authors.initials: A
authors.lastname: Dawn
authors.affiliation: Malaria Group, International Centre for Genetic Engineering and Biotechnology (ICGEB), New Delhi, India; Malaria Parasite Biology and Vaccines Unit, Department of Parasites and Insect Vectors, Institut Pasteur, Paris, France.
authors.forename: Shailja
authors.initials: S
authors.lastname: Singh
authors.affiliation: Malaria Group, International Centre for Genetic Engineering and Biotechnology (ICGEB), New Delhi, India.
authors.forename: Kunal R
authors.initials: KR
authors.lastname: More
authors.affiliation: Malaria Group, International Centre for Genetic Engineering and Biotechnology (ICGEB), New Delhi, India.
authors.forename: Faiza Amber
authors.initials: FA
authors.lastname: Siddiqui
authors.affiliation: Malaria Group, International Centre for Genetic Engineering and Biotechnology (ICGEB), New Delhi, India.
authors.forename: Niseema
authors.initials: N
authors.lastname: Pachikara
authors.affiliation: Laboratoire de Biologie Cellulaire Comparative des Apicomplexes, Institut Cochin, INSERM U1016, CNRS UMR 8104, Paris, France.
authors.forename: Ghania
authors.initials: G
authors.lastname: Ramdani
authors.affiliation: Laboratoire de Biologie Cellulaire Comparative des Apicomplexes, Institut Cochin, INSERM U1016, CNRS UMR 8104, Paris, France.
authors.forename: Gordon
authors.initials: G
authors.lastname: Langsley
authors.affiliation: Malaria Group, International Centre for Genetic Engineering and Biotechnology (ICGEB), New Delhi, India; Malaria Parasite Biology and Vaccines Unit, Department of Parasites and Insect Vectors, Institut Pasteur, Paris, France.
authors.forename: Chetan E
authors.initials: CE
authors.lastname: Chitnis
mesh_terms: D002118:Calcium / Q000502:physiology; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000502:physiology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology; D004912:Erythrocytes / Q000187:drug effects / Q000469:parasitology* / Q000473:pathology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D016778:Malaria, Falciparum / Q000503:physiopathology*; D052940:Merozoites / Q000254:growth & development* / Q000502:physiology; D010963:Plasmodium falciparum / Q000472:pathogenicity*; D011188:Potassium / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology
chemical_list: D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D011188:Potassium; D002118:Calcium