Molecular cloning of a K+ channel from the malaria parasite Plasmodium falciparum

Ellekvist, Peter; Ricke, Christina H.; Litman, Thomas; Salanti, Ali; Colding, Hanne; Zeuthen, Thomas; Klærke, Dan A.

doi:10.1016/j.bbrc.2004.04.049

Cited by 25 publications

(23 citation statements)

References 20 publications

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“…The nonspecific K ϩ channel blocker tetraethylammonium (TEA; 20 mM) had a small and nonsignificant inhibitory effect on 86 Rb ϩ uptake in WT parasites, suggesting that PbKch1 is insensitive to TEA. In a recent study (19), it has been shown that exposure of P. berghei sporozoites to intracellular concentrations of K ϩ enhances their infectivity by [8][9][10] times. This effect of a high K ϩ concentration is significantly attenuated by K ϩ channel blockers, including TEA.…”

Section: Resultsmentioning

confidence: 99%

“…K ϩ channels constitute the largest and most diverse of ion channel families and are involved in K ϩ transport, cell volume control, and regulation of membrane potential. Two putative K ϩ channel-encoding genes have been found in the P. falciparum genome (10)(11), but it remains to be established whether they are functional and whether they are important for parasite survival. So far attempts to express and functionally characterize Plasmodium K ϩ channels in heterologous cell systems have been unsuccessful.…”

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confidence: 99%

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Critical role of a K ⁺ channel in Plasmodium berghei transmission revealed by targeted gene disruption

Ellekvist¹,

Maciel

Mlambo

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Regulated K ؉ transport across the plasma membrane is of vital importance for the survival of most cells. Two K ؉ channels have been identified in the Plasmodium falciparum genome; however, their functional significance during parasite life cycle in the vertebrate host and during transmission through the mosquito vector remains unknown. We hypothesize that these two K ؉ channels mediate the transport of K ؉ in the parasites, and thus are important for parasite survival. To test this hypothesis, we identified the orthologue of one of the P. falciparum K ؉ channels, PfKch1, in the rodent malaria parasite P. berghei (PbKch1) and examined the biological role by performing a targeted disruption of the gene encoding PbKch1. The deduced amino acid sequence of the six transmembrane domains of PfKch1 and PbKch1 share 82% identity, and in particular the pore regions are completely identical. The PbKch1-null parasites were viable despite a marked reduction in the uptake of the K ؉ congener 86 Rb ؉ , and mice infected with PbKch1-null parasites survived slightly longer than mice infected with WT parasites. However, the most striking feature of the phenotype was the virtually complete inhibition of the development of PbKch1-null parasites in Anopheles stephensi mosquitoes. In conclusion, these studies demonstrate that PbKch1 contributes to the transport of K ؉ in P. berghei parasites and supports the growth of the parasites, in particular the development of oocysts in the mosquito midgut. K ؉ channels therefore may constitute a potential antimalarial drug target. malaria ͉ pathogenesis ͉ mosquito ͉ drug target

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Critical role of a K ⁺ channel in Plasmodium berghei transmission revealed by targeted gene disruption

Ellekvist¹,

Maciel

Mlambo

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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“…Plasmodium falciparum, an important human protozoan pathogen, have been cloned and characterized at the molecular level [Ellekvist et al, 2004;Waller et al, 2008b]. Furthermore, sexual reproduction of the mosquito-stage of Plasmodium bergei seems to be impaired by gene disruption of pbKch1, the homologous gene for pfKch1 (PfK1) in this parasite [Ellekvist et al, 2008], suggesting that K In Trypanosoma cruzi, the causative agent of Chagas disease, K þ conductive pathways have been postulated to play a role in osmoregulatory process, contributing to 7% of the regulatory volume decrease observed under hyposmotic stress [reviewed in Rohloff and Docampo, 2008].…”

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Electrophysiological characterization of potassium conductive pathways in Trypanosoma cruzi

Jiménez

Henríquez

Galanti

et al. 2011

J of Cellular Biochemistry

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Potassium channels (K(+) channels) are members of one of the largest and most diverse families of membrane proteins, widely described from bacteria to humans. Their functions include voltage-membrane potential maintenance, pH and cell volume regulation, excitability, organogenesis and cell death. K(+) channels are involved in sensing and responding to environmental changes such as acidification, O(2) pressure, osmolarity, and ionic concentration. Trypanosoma cruzi is a parasitic protozoan, causative agent of Chagas disease (American trypanosomiasis) an endemic pathology in Latin America, where up 200,000 new cases are reported annually. In protozoan parasites, the presence of K(+) channels has been suggested, but functional direct evidence supporting this hypothesis is limited, mainly due to the difficulty of employing conventional electrophysiological methods to intact parasites. In T. cruzi, K(+) conductive pathways are thought to contribute in the regulatory volume decrease observed under hypoosmotic stress, the steady state pH and the compensatory response to extracellular acidification and the maintenance of plasma membrane potential. In this work we describe the isolation of plasma membrane enriched fractions from T. cruzi epimastigotes, their reconstitution into giant liposomes and the first functional characterization by patch-clamp of K(+) conductive pathways in protozoan parasites.

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“…Little is known about how the parasites import inorganic nutrients. The malaria parasite Plasmodium falciparum possesses two putative K ϩ channel subunits with 6 TM domains and one P-loop (19,52). Disruption of an orthologous gene in Plasmodium berghei strongly impaired the development of the malaria parasites in the mosquito (18).…”

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A Trk/HKT-Type K ⁺ Transporter from Trypanosoma brucei

et al. 2010

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The molecular mechanisms of K ؉ homeostasis are only poorly understood for protozoan parasites. Trypanosoma brucei subsp. parasites, the causative agents of human sleeping sickness and nagana, are strictly extracellular and need to actively concentrate K ؉ from their hosts' body fluids. The T. brucei genome contains two putative K ؉ channel genes, yet the trypanosomes are insensitive to K ؉ antagonists and K ؉ channelblocking agents, and they do not spontaneously depolarize in response to high extracellular K ؉ concentrations. However, the trypanosomes are extremely sensitive to K ؉ ionophores such as valinomycin. Surprisingly, T. brucei possesses a member of the Trk/HKT superfamily of monovalent cation permeases which so far had only been known from bacteria, archaea, fungi, and plants. The protein was named TbHKT1 and functions as a Na ؉ -independent K ؉ transporter when expressed in Escherichia coli, Saccharomyces cerevisiae, or Xenopus laevis oocytes. In trypanosomes, TbHKT1 is expressed in both the mammalian bloodstream stage and the Tsetse fly midgut stage; however, RNA interference (RNAi)-mediated silencing of TbHKT1 expression did not produce a growth phenotype in either stage. The presence of HKT genes in trypanosomatids adds a further piece to the enigmatic phylogeny of the Trk/HKT superfamily of K ؉ transporters. Parsimonial analysis suggests that the transporters were present in the first eukaryotes but subsequently lost in several of the major eukaryotic lineages, in at least four independent events.

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Molecular cloning of a K+ channel from the malaria parasite Plasmodium falciparum

Cited by 25 publications

References 20 publications

Critical role of a K ⁺ channel in Plasmodium berghei transmission revealed by targeted gene disruption

Critical role of a K ⁺ channel in Plasmodium berghei transmission revealed by targeted gene disruption

Electrophysiological characterization of potassium conductive pathways in Trypanosoma cruzi

A Trk/HKT-Type K ⁺ Transporter from Trypanosoma brucei

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Molecular cloning of a K+ channel from the malaria parasite Plasmodium falciparum

Cited by 25 publications

References 20 publications

Critical role of a K + channel in Plasmodium berghei transmission revealed by targeted gene disruption

Critical role of a K + channel in Plasmodium berghei transmission revealed by targeted gene disruption

Electrophysiological characterization of potassium conductive pathways in Trypanosoma cruzi

A Trk/HKT-Type K + Transporter from Trypanosoma brucei

Contact Info

Product

Resources

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Critical role of a K ⁺ channel in Plasmodium berghei transmission revealed by targeted gene disruption

Critical role of a K ⁺ channel in Plasmodium berghei transmission revealed by targeted gene disruption

A Trk/HKT-Type K ⁺ Transporter from Trypanosoma brucei