scholarly journals Decreased glutamate transport in acivicin resistant Leishmania tarentolae

2021 ◽  
Vol 15 (12) ◽  
pp. e0010046
Author(s):  
Gaétan Roy ◽  
Arijit Bhattacharya ◽  
Philippe Leprohon ◽  
Marc Ouellette

Studies of drug resistance in the protozoan parasites of the genus Leishmania have been helpful in revealing biochemical pathways as potential drug targets. The chlorinated glutamine analogue acivicin has shown good activity against Leishmania cells and was shown to target several enzymes containing amidotransferase domains. We selected a Leishmania tarentolae clone for acivicin resistance. The genome of this resistant strain was sequenced and the gene coding for the amidotransferase domain-containing GMP synthase was found to be amplified. Episomal expression of this gene in wild-type L. tarentolae revealed a modest role in acivicin resistance. The most prominent defect observed in the resistant mutant was reduced uptake of glutamate, and through competition experiments we determined that glutamate and acivicin, but not glutamine, share the same transporter. Several amino acid transporters (AATs) were either deleted or mutated in the resistant cells. Some contributed to the acivicin resistance phenotype although none corresponded to the main glutamate transporter. Through sequence analysis one AAT on chromosome 22 corresponded to the main glutamate transporter. Episomal expression of the gene coding for this transporter in the resistant mutant restored glutamate transport and acivicin susceptibility. Its genetic knockout led to reduced glutamate transport and acivicin resistance. We propose that acivicin binds covalently to this transporter and as such leads to decreased transport of glutamate and acivicin thus leading to acivicin resistance.

2011 ◽  
Vol 32 (4) ◽  
pp. 144
Author(s):  
Eleanor Saunders ◽  
David De Souza ◽  
James McRae ◽  
Vladimir Likic ◽  
Malcolm McConville

Protozoan parasites cause a number of important diseases in humans, including malaria, African trypanosomiasis, Chagas disease and the leishmaniases. Current therapeutics for these diseases are limited and their effectiveness is being further undermined by the emergence of drug-resistant parasite strains. Parasite genome sequencing projects have provided new insights into the metabolic capacity of these pathogens and have highlighted potential drug targets. However, these genome-based reconstructions of metabolic networks are incomplete and we still have only a limited understanding of the metabolic requirements of these pathogens during infection. Metabolomics has emerged as a powerful new tool for investigating parasite metabolism and host responses, complementing more established omics technologies as well as being useful as a stand-alone technique.


2009 ◽  
Vol 101 (3) ◽  
pp. 1179-1191 ◽  
Author(s):  
Ewa D. Zarnowska ◽  
Ruth Keist ◽  
Uwe Rudolph ◽  
Robert A. Pearce

γ-Aminobutyric acid type A (GABAA) receptor α5 subunits, which are heavily expressed in the hippocampus, are potential drug targets for improving cognitive function. They are found at synaptic and extrasynaptic sites and have been shown to mediate tonic inhibition in pyramidal neurons. We tested the hypothesis that α5 subunits also contribute to synaptic inhibition by measuring the effect of diazepam (DZ) on spontaneous and stimulus-evoked inhibitory postsynaptic currents (IPSCs) in genetically modified mice carrying a point mutation in the α5 subunit (α5-H105R) that renders those receptors insensitive to benzodiazepines. In wild type mice, DZ (1 μM) increased the amplitude of spontaneous IPSCs (sIPSCs) and stimulus-evoked GABAA,slow IPSCs (eIPSCs) and prolonged the decay of GABAA,fast sIPSCs. In α5-mutant mice, DZ increased the amplitude of a small-amplitude subset of sIPSCs (<50 pA) and eIPSCs (<300 pA) GABAA,slow and prolonged the decay of GABAA,fast sIPSCs, but failed to increase the amplitude of larger sIPSCs and eIPSCs GABAA,slow. These results indicate that α5 subunits contribute to a large-amplitude subset of GABAA,slow synapses and implicate these synapses in modulation of cognitive function by drugs that target α5 subunits.


2021 ◽  
Vol 15 ◽  
Author(s):  
Xiang Li ◽  
Wenjun Wang ◽  
Jianghong Yan ◽  
Fancai Zeng

Parkinson’s disease (PD) is a common neurodegenerative disease in middle-aged and elderly individuals. At present, no effective drug has been developed to treat PD. Although a variety of drugs exist for the symptomatic treatment of PD, they all have strong side effects. Most studies on PD mainly focus on dopaminergic neurons. This review highlights the function of glutamic acid transporters (GLTs), including excitatory amino acid transporters (EAATs) and vesicular glutamate transporters (VGLUTs), during the development of PD. In addition, using bioinformatics, we compared the expression of different types of glutamate transporter genes in the cingulate gyrus of PD patients and healthy controls. More importantly, we suggest that the functional roles of glutamate transporters may prove beneficial in the treatment of PD. In summary, VGLUTs and EAATs may be potential targets in the treatment of PD. VGLUTs and EAATs can be used as clinical drug targets to achieve better efficacy. Through this review article, we hope to enable future researchers to improve the condition of PD patients.


2014 ◽  
Vol 15 (3) ◽  
pp. 255-271 ◽  
Author(s):  
Rubem Sadok Menna-Barreto ◽  
Kele Belloze ◽  
Jonas Perales ◽  
Floriano Silva-Jr

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