cyclic-gmp and Malaria

Malaria-causing parasites are transmitted from humans to mosquitoes when developmentally arrested gametocytes are taken up by a female Anopheles during a blood meal. The changes in environment from human to mosquito activate gametogenesis, including a drop in temperature, a rise in pH, and a mosquito-derived molecule, xanthurenic acid. Signaling receptors have not been identified in malaria parasites but mounting evidence indicates that cGMP homeostasis is key to sensing extracellular cues in gametocytes. Low levels of cGMP maintained by phosphodiesterases prevent precocious activation of gametocytes in the human blood. Upon ingestion, initiation of gametogenesis depends on the activation of a hybrid guanylyl cyclase/P4-ATPase. Elevated cGMP levels lead to the rapid mobilization of intracellular calcium that relies upon the activation of both cGMP-dependent protein kinase and phosphoinositide phospholipase C. Once calcium is released, a cascade of phosphorylation events mediated by calcium-dependent protein kinases and phosphatases regulates the cellular processes required for gamete formation. cGMP signaling also triggers timely egress from the host cell at other life cycle stages of malaria parasites and in Toxoplasma gondii, a related apicomplexan parasite. This suggests that cGMP signaling is a versatile platform transducing external cues into calcium signals at important decision points in the life cycle of apicomplexan parasites.

Topics: Animals; Anopheles; Calcium; Cyclic GMP; Germ Cells; Humans; Life Cycle Stages; Malaria; Plasmodium; Protozoan Proteins

Gametogenesis is an essential step for malaria parasite transmission and is activated in mosquito by signals including temperature drop, pH change, and mosquito-derived xanthurenic acid (XA). Recently, a membrane protein gametogenesis essential protein 1 (GEP1) was found to be responsible for sensing these signals and interacting with a giant guanylate cyclase α (GCα) to activate the cGMP-PKG-Ca

Topics: Animals; Cyclic GMP; Gametogenesis; Guanylate Cyclase; Malaria; Molecular Docking Simulation; Parasites; Signal Transduction

Guanylyl cyclases (GCs) synthesize cyclic GMP (cGMP) and, together with cyclic nucleotide phosphodiesterases, are responsible for regulating levels of this intracellular messenger which mediates myriad functions across eukaryotes. In malaria parasites (

Topics: Adenosine Triphosphatases; Cyclic GMP; Erythrocytes; Guanylate Cyclase; Humans; Malaria; Merozoites; Plasmodium falciparum; Protein Domains; Protozoan Proteins; Signal Transduction

Gametocytes differentiation to gametes (gametogenesis) within mosquitos is essential for malaria parasite transmission. Both reduction in temperature and mosquito-derived XA or elevated pH are required for triggering cGMP/PKG dependent gametogenesis. However, the parasite molecule for sensing or transducing these environmental signals to initiate gametogenesis remains unknown. Here we perform a CRISPR/Cas9-based functional screening of 59 membrane proteins expressed in the gametocytes of Plasmodium yoelii and identify that GEP1 is required for XA-stimulated gametogenesis. GEP1 disruption abolishes XA-stimulated cGMP synthesis and the subsequent signaling and cellular events, such as Ca

Topics: Animals; Calcium; CRISPR-Cas Systems; Culicidae; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Gametogenesis; Gene Editing; Intracellular Membranes; Malaria; Mosquito Vectors; Plasmodium; Protozoan Proteins; Xanthurenates

The cyclic guanosine-3',5'-monophosphate (cGMP)-dependent protein kinase (PKG) was identified >25 y ago; however, efforts to obtain a structure of the entire PKG enzyme or catalytic domain from any species have failed. In malaria parasites, cooperative activation of PKG triggers crucial developmental transitions throughout the complex life cycle. We have determined the cGMP-free crystallographic structures of PKG from

Topics: Amino Acid Sequence; Animals; Binding Sites; Catalytic Domain; Crystallography, X-Ray; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Humans; Kinetics; Malaria; Plasmodium falciparum; Protein Binding; Protein Conformation

When ingested by a mosquito, the malaria parasite relies on an unusual form of gliding motility to escape from the rapidly deteriorating blood meal. A new study on an atypical malaria guanylyl cyclase reveals the importance of spatiotemporal regulation of cGMP production in this process.

Topics: Animals; Cyclic GMP; Guanylate Cyclase; Malaria; Signal Transduction

Cyclic nucleotide-specific phosphodiesterases (PDEs) have come into focus as interesting potential targets for PDE inhibitor-based anti-parasitic drugs. Genomes of the various agents of human malaria, most notably Plasmodium falciparum, all contain four genes for class 1 PDEs. The catalytic domains of these enzymes are closely related to those of the 11 human PDE families. This presents the possibility that the available vast expertise in developing drugs against human PDEs might now also be applied to developing compounds that are active against malarial PDEs. The current study identifies four Plasmodium genes that code for PfPDEalpha, PfPDEbeta, PfPDEgamma and PfPDEdelta, respectively. It further demonstrates that the PfPDEalpha polypeptide exists in two versions (PfPDEalphaA and PfPDEalphaB) that are generated by alternative splicing of the primary transcript. All malarial PDEs contain several transmembrane helices in their N-terminal regions, indicating that they are integral membrane proteins. In agreement with this prediction, essentially all PDE activity is associated with the cell membranes. PfPDEalpha was characterized as a cGMP-specific PDE that is not sensitive to a number of standard PDE inhibitors. Genetic ablation of the PfPDE1 gene produced no major phenotype in erythrocyte cultures.

Topics: Animals; Blotting, Southern; Cyclic GMP; Enzyme Inhibitors; Gene Expression Regulation, Enzymologic; Malaria; Membrane Proteins; Molecular Sequence Data; Phosphoric Diester Hydrolases; Plasmodium falciparum; Polymerase Chain Reaction; Protozoan Proteins