scholarly journals Malaria Parasite cGMP-dependent Protein Kinase Regulates Blood Stage Merozoite Secretory Organelle Discharge and Egress

2013 ◽  
Vol 9 (5) ◽  
pp. e1003344 ◽  
Author(s):  
Christine R. Collins ◽  
Fiona Hackett ◽  
Malcolm Strath ◽  
Maria Penzo ◽  
Chrislaine Withers-Martinez ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Malaria Parasite ◽  
Blood Stage ◽  
Dependent Protein Kinase ◽  
Cgmp Dependent Protein Kinase ◽  
Dependent Protein

scholarly journals The Malaria Parasite Cyclic GMP-Dependent Protein Kinase Plays a Central Role in Blood-Stage Schizogony

2009 ◽  
Vol 9 (1) ◽  
pp. 37-45 ◽  
Author(s):  
Helen M. Taylor ◽  
Louisa McRobert ◽  
Munira Grainger ◽  
Audrey Sicard ◽  
Anton R. Dluzewski ◽  
...  
Keyword(s):  
Life Cycle ◽  
Protein Kinase ◽  
Cyclic Gmp ◽  
Malaria Parasite ◽  
Kinase Inhibitor ◽  
Blood Stage ◽  
Parasite Life Cycle ◽  
Dependent Protein Kinase ◽  
Asexual Blood Stage ◽  
Dependent Protein

ABSTRACT A role for the Plasmodium falciparum cyclic GMP (cGMP)-dependent protein kinase (PfPKG) in gametogenesis in the malaria parasite was elucidated previously. In the present study we examined the role of PfPKG in the asexual blood-stage of the parasite life cycle, the stage that causes malaria pathology. A specific PKG inhibitor (compound 1, a trisubstituted pyrrole) prevented the progression of P. falciparum schizonts through to ring stages in erythrocyte invasion assays. Addition of compound 1 to ring-stage parasites allowed normal development up to 30 h postinvasion, and segmented schizonts were able to form. However, synchronized schizonts treated with compound 1 for ≥6 h became large and dysmorphic and were unable to rupture or liberate merozoites. To conclusively demonstrate that the effect of compound 1 on schizogony was due to its selective action on PfPKG, we utilized genetically manipulated P. falciparum parasites expressing a compound 1-insensitive PfPKG. The mutant parasites were able to complete schizogony in the presence of compound 1 but not in the presence of the broad-spectrum protein kinase inhibitor staurosporine. This shows that PfPKG is the primary target of compound 1 during schizogony and provides direct evidence of a role for PfPKG in this process. Discovery of essential roles for the P. falciparum PKG in both asexual and sexual development demonstrates that cGMP signaling is a key regulator of both of these crucial life cycle phases and defines this molecule as an exciting potential drug target for both therapeutic and transmission blocking action against malaria.

scholarly journals The role of the cGMP-dependent protein kinase in development of the malaria parasite

2009 ◽  
Vol 9 (Suppl 1) ◽  
pp. S2
Author(s):  
Louisa McRobert ◽  
Helen M Taylor ◽  
Cathy J Taylor ◽  
Wensheng Deng ◽  
Robert W Moon ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Malaria Parasite ◽  
Dependent Protein Kinase ◽  
Cgmp Dependent Protein Kinase ◽  
Dependent Protein

scholarly journals Targeting the Malaria Parasite cGMP-Dependent Protein Kinase to Develop New Drugs

2020 ◽  
Vol 11 ◽  
Author(s):  
David A. Baker ◽  
Alexios N. Matralis ◽  
Simon A. Osborne ◽  
Jonathan M. Large ◽  
Maria Penzo
Keyword(s):  
Life Cycle ◽  
Protein Kinase ◽  
Malaria Parasite ◽  
Public Health Problem ◽  
Major Public Health Problem ◽  
Parasite Life Cycle ◽  
Dependent Protein Kinase ◽  
Cgmp Dependent Protein Kinase ◽  
Cgmp Signaling ◽  
Dependent Protein

The single-celled apicomplexan parasite Plasmodium falciparum is responsible for the majority of deaths due to malaria each year. The selection of drug resistance has been a recurring theme over the decades with each new drug that is developed. It is therefore crucial that future generations of drugs are explored to tackle this major public health problem. Cyclic GMP (cGMP) signaling is one of the biochemical pathways that is being explored as a potential target for new antimalarial drugs. It has been shown that this pathway is essential for all of the key developmental stages of the complex malaria parasite life cycle. This gives hope that targeting cGMP signaling might give rise to drugs that treat disease, block its transmission and even prevent the establishment of infection. Here we review previous work that has been carried out to develop and optimize inhibitors of the cGMP-dependent protein kinase (PKG) which is a critical regulator of the malaria parasite life cycle.

cDNA Cloning and Gene Expression of Human Type Iα cGMP-Dependent Protein Kinase

Hypertension ◽  
1996 ◽  
Vol 27 (3) ◽  
pp. 552-557 ◽  
Author(s):  
Naohisa Tamura ◽  
Hiroshi Itoh ◽  
Yoshihiro Ogawa ◽  
Osamu Nakagawa ◽  
Masaki Harada ◽  
...  
Keyword(s):  
Gene Expression ◽  
Protein Kinase ◽  
Cdna Cloning ◽  
Dependent Protein Kinase ◽  
Human Type ◽  
Cgmp Dependent Protein Kinase ◽  
Dependent Protein

scholarly journals The cGMP-Dependent Protein Kinase 2 Contributes to Cone Photoreceptor Degeneration in the Cnga3-Deficient Mouse Model of Achromatopsia

2020 ◽  
Vol 22 (1) ◽  
pp. 52
Author(s):  
Mirja Koch ◽  
Constanze Scheel ◽  
Hongwei Ma ◽  
Fan Yang ◽  
Michael Stadlmeier ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Mouse Model ◽  
Cyclic Guanosine Monophosphate ◽  
Guanosine Monophosphate ◽  
Cone Photoreceptor ◽  
Photoreceptor Degeneration ◽  
Dependent Protein Kinase ◽  
Genetic Ablation ◽  
Cgmp Dependent Protein Kinase ◽  
Dependent Protein

Mutations in the CNGA3 gene, which encodes the A subunit of the cyclic guanosine monophosphate (cGMP)-gated cation channel in cone photoreceptor outer segments, cause total colour blindness, also referred to as achromatopsia. Cones lacking this channel protein are non-functional, accumulate high levels of the second messenger cGMP and degenerate over time after induction of ER stress. The cell death mechanisms that lead to loss of affected cones are only partially understood. Here, we explored the disease mechanisms in the Cnga3 knockout (KO) mouse model of achromatopsia. We found that another important effector of cGMP, the cGMP-dependent protein kinase 2 (Prkg2) is crucially involved in cGMP cytotoxicity of cones in Cnga3 KO mice. Virus-mediated knockdown or genetic ablation of Prkg2 in Cnga3 KO mice counteracted degeneration and preserved the number of cones. Analysis of markers of endoplasmic reticulum stress and unfolded protein response confirmed that induction of these processes in Cnga3 KO cones also depends on Prkg2. In conclusion, we identified Prkg2 as a novel key mediator of cone photoreceptor degeneration in achromatopsia. Our data suggest that this cGMP mediator could be a novel pharmacological target for future neuroprotective therapies.

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