Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: EC:2.7.11.12 (
PKG
)
2,515
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
The coccidian parasite
cGMP-dependent protein kinase
is the primary target of a novel coccidiostat, the trisubstituted pyrrole 4-[2-(4-fluorophenyl)-5-(1-methylpiperidine-4-yl)-1H-pyrrol-3-yl] pyridine (compound 1), which effectively controls the proliferation of Eimeria tenella and Toxoplasma gondii parasites in animal models. The efficacy of compound 1 in parasite-specific metabolic assays of infected host cell monolayers is critically dependent on the timing of compound addition. Simultaneous addition of compound with extracellular E. tenella sporozoites or T. gondii tachyzoites inhibited [3H]-uracil uptake in a dose-dependent manner, while minimal efficacy was observed if compound addition was delayed, suggesting a block in host cell invasion. Immunofluorescence assays confirmed that compound 1 blocks the attachment of Eimeria sporozoites or Toxoplasma tachyzoites to host cells and inhibits parasite invasion and gliding motility. Compound 1 also inhibits the secretion of micronemal adhesins (E. tenella MIC1,
MIC2
and T. gondii
MIC2
), an activity closely linked to invasion and motility in apicomplexan parasites. The inhibition of T. gondii
MIC2
adhesin secretion by compound 1 was not reversed by treatment with calcium ionophores or by ethanol (a microneme secretagogue), suggesting a block downstream of calcium-dependent events commonly associated with the discharge of the microneme organelle in tachyzoites. Transgenic Toxoplasma strains expressing
cGMP-dependent protein kinase
mutant alleles that are refractory to compound 1 (including
cGMP-dependent protein kinase
knock-out lines complemented by such mutants) were used as tools to validate the potential role of
cGMP-dependent protein kinase
in invasion and motility. In these strains, parasite adhesin secretion, gliding motility, host cell attachment and invasion displayed a reduced sensitivity to compound 1. These data clearly demonstrate that
cGMP-dependent protein kinase
performs an important role in the host-parasite interaction.
...
PMID:A role for coccidian cGMP-dependent protein kinase in motility and invasion. 1500 97
Research has shown that estrogen is present and plays a critical role in vertebrate reproduction and metabolism, but the influence of steroids on
Toxoplasma gondii
has received less attention. Our data showed that estradiol and progesterone induced parasitic cytosolic Ca
2+
fluxes. This process required estrogen to enter the cytoplasm of
T. gondii
, and
cGMP-dependent protein kinase
G (PKG) and phosphoinositide-phospholipase C (PI-PLC) emerged as important factors controlling parasitic intracellular (IC) Ca
2+
signals. Cytosolic Ca
2+
, which is regulated by estradiol, was mostly mobilized from acidic organelles. Moreover, cytosolic Ca
2+
slightly increased
MIC2
protein secretion and promoted the gliding motility and egress of parasites, thus enhancing the pathogenicity of
T. gondii
, as shown in our previous research. We subsequently determined that the main source of Ca
2+
regulated by progesterone was a neutral store. In contrast to the findings of estradiol, progesterone reduced
MIC2
protein secretion and inhibited the gliding motility of parasites, which may decrease their pathogenicity. Additionally, unlike in mammals, estradiol and progesterone had no effect on nitric oxide (NO) or reactive oxygen species (ROS) production in
T. gondii
.
...
PMID:Effects of Estradiol and Progesterone-Induced Intracellular Calcium Fluxes on
Toxoplasma gondii
Gliding, Microneme Secretion, and Egress. 2994 11
