Identification of Putative Potassium Channel Homologues in Pathogenic Protozoa

Prole, David L.; Marrion, Neil V.

doi:10.1371/journal.pone.0032264

Cited by 25 publications

(20 citation statements)

References 146 publications

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“…Each subunit is predicted to contain eight transmembrane domains (TMDs), with two predicted selectivity filter regions, separated by two TMDs ( Figure 2A ) [34], [54], [55]. This predicted structure differs from the two-pore K + channel subunits of other organisms, which have only four TMDs arranged like the last four TMDs of the larger fungal subunits [55]–[58]. Both types of two-pore channel are likely formed by dimerization of subunits [59], [60], which allows four pore-forming loops to create a central pore akin to that of mammalian K + channels [56].…”

Section: Resultsmentioning

confidence: 99%

Identification and Analysis of Cation Channel Homologues in Human Pathogenic Fungi

Prole

Taylor

2012

PLoS ONE

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Fungi are major causes of human, animal and plant disease. Human fungal infections can be fatal, but there are limited options for therapy, and resistance to commonly used anti-fungal drugs is widespread. The genomes of many fungi have recently been sequenced, allowing identification of proteins that may become targets for novel therapies. We examined the genomes of human fungal pathogens for genes encoding homologues of cation channels, which are prominent drug targets. Many of the fungal genomes examined contain genes encoding homologues of potassium (K+), calcium (Ca2+) and transient receptor potential (Trp) channels, but not sodium (Na+) channels or ligand-gated channels. Some fungal genomes contain multiple genes encoding homologues of K+ and Trp channel subunits, and genes encoding novel homologues of voltage-gated Kv channel subunits are found in Cryptococcus spp. Only a single gene encoding a homologue of a plasma membrane Ca2+ channel was identified in the genome of each pathogenic fungus examined. These homologues are similar to the Cch1 Ca2+ channel of Saccharomyces cerevisiae. The genomes of Aspergillus spp. and Cryptococcus spp., but not those of S. cerevisiae or the other pathogenic fungi examined, also encode homologues of the mitochondrial Ca2+ uniporter (MCU). In contrast to humans, which express many K+, Ca2+ and Trp channels, the genomes of pathogenic fungi encode only very small numbers of K+, Ca2+ and Trp channel homologues. Furthermore, the sequences of fungal K+, Ca2+, Trp and MCU channels differ from those of human channels in regions that suggest differences in regulation and susceptibility to drugs.

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Section: Resultsmentioning

confidence: 99%

Identification and Analysis of Cation Channel Homologues in Human Pathogenic Fungi

Prole

Taylor

2012

PLoS ONE

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“…Many chemical blockers of mammalian K + channels interact with the pore region [9]. The predicted pore regions of Kch1 and Kch2 differ in several aspects from the pore regions of mammalian K + channels, and it should be possible to identify specific inhibitors of Plasmodium K + channels without affecting human K + channels [10]. However, identification of such agents requires a robust assay for the Plasmodium K + channels in a suitable heterologous expression system, at task which has so far not been accomplished.…”

Section: Discussionmentioning

confidence: 99%

Functional characterization of malaria parasites deficient in the K+ channel Kch2

Ellekvist

Mlambo

Kumar

et al. 2017

Biochemical and Biophysical Research Communications

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K+ channels are integral membrane proteins, which contribute to maintain vital parameters such as the cellular membrane potential and cell volume. Malaria parasites encode two K+ channel homologues, Kch1 and Kch2, which are well-conserved among members of the Plasmodium genus. In the rodent malaria parasite P. berghei, the functional significance of K+ channel homologue PbKch2 was studied using targeted gene knock-out. The knockout parasites were characterized in a mouse model in terms of growth-kinetics and infectivity in the mosquito vector. Furthermore, using a tracer-uptake technique with 86Rb+ as a K+ congener, the K+ transporting properties of the knockout parasites were assessed. Results Genetic disruption of Kch2 did not grossly affect the phenotype in terms of asexual replication and pathogenicity in a mouse model. In contrast to Kch1-null parasites, Kch2-null parasites were fully capable of forming oocysts in female Anopheles stephensi mosquitoes. 86Rb+ uptake in Kch2-deficient blood-stage P. berghei parasites (Kch2-null) did not differ from that of wild-type (WT) parasites. About two-third of the 86Rb+ uptake in WT and in Kch2-null parasites could be inhibited by K+ channel blockers and could be inferred to the presence of functional Kch1 in Kch2 knockout parasites. Kch2 is therefore not required for transport of K+ in P. berghei and is not essential to mosquito-stage sporogonic development of the parasite.

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“…They are large proteins (∼1500–4700 residues) with many predicted transmembrane domains (TMDs) (∼18–44) distributed throughout their sequences [6]. Their existence has been reported in vertebrates, plants, nematodes, insects, amoebae and free-living ciliates, but they are absent from many fungi [6], [51], [52]. We found that genes encoding homologues of Piezo are present in the genomes of E. histolytica , Leishmania spp., Trypanosoma cruzi and T. vaginalis , but they are absent from Trypanosoma brucei , G. intestinalis and the apicomplexan parasites examined ( Table 1 ).…”

Section: Resultsmentioning

confidence: 90%

“…Analyses of genomes, sequence alignments and topology analysis were conducted as reported previously [1], [50]. BLASTP and TBLASTN searches of protozoan genomes were carried out against the National Center for Biotechnology (NCBI) genomic protein databases.…”

Section: Methodsmentioning

confidence: 99%

“…The mid1 -complementing activity (MCA) proteins of plants may also be mechanosensitive Ca 2+ channels [15], [48]. We and others have previously reported the presence of genes encoding putative Trp channels [1], [49], but not K 2P channels [50], in the genomes of pathogenic protozoa. It is possible that some of the protozoan Trp channels are mechanosensitive, although this will require experimental analysis as many Trp channels are modulated by other stimuli [40]–[42].…”

Section: Introductionmentioning

confidence: 99%

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Identification and Analysis of Putative Homologues of Mechanosensitive Channels in Pathogenic Protozoa

Prole

Taylor

2013

PLoS ONE

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Mechanosensitive channels play important roles in the physiology of many organisms, and their dysfunction can affect cell survival. This suggests that they might be therapeutic targets in pathogenic organisms. Pathogenic protozoa lead to diseases such as malaria, dysentery, leishmaniasis and trypanosomiasis that are responsible for millions of deaths each year worldwide. We analyzed the genomes of pathogenic protozoa and show the existence within them of genes encoding putative homologues of mechanosensitive channels. Entamoeba histolytica, Leishmania spp., Trypanosoma cruzi and Trichomonas vaginalis have genes encoding homologues of Piezo channels, while most pathogenic protozoa have genes encoding homologues of mechanosensitive small-conductance (MscS) and K+-dependent (MscK) channels. In contrast, all parasites examined lack genes encoding mechanosensitive large-conductance (MscL), mini-conductance (MscM) and degenerin/epithelial Na+ (DEG/ENaC) channels. Multiple sequence alignments of evolutionarily distant protozoan, amoeban, plant, insect and vertebrate Piezo channel subunits define an absolutely conserved motif that may be involved in channel conductance or gating. MscS channels are not present in humans, and the sequences of protozoan and human homologues of Piezo channels differ substantially. This suggests the possibility for specific targeting of mechanosensitive channels of pathogens by therapeutic drugs.

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Identification of Putative Potassium Channel Homologues in Pathogenic Protozoa

Cited by 25 publications

References 146 publications

Identification and Analysis of Cation Channel Homologues in Human Pathogenic Fungi

Identification and Analysis of Cation Channel Homologues in Human Pathogenic Fungi

Functional characterization of malaria parasites deficient in the K+ channel Kch2

Identification and Analysis of Putative Homologues of Mechanosensitive Channels in Pathogenic Protozoa

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