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

Peter Ellekvist; Jorge Maciel; Godfree Mlambo; Christina Høier Ricke; Hanne Colding; Dan Arne Klaerke; Nirbhay Kumar

doi:10.1073/pnas.0802384105

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

Peter Ellekvist, Jorge Maciel, Godfree Mlambo, Christina Høier Ricke, Hanne Colding, Dan Arne Klaerke, Nirbhay Kumar

22 Citations (Scopus)

Abstract

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.

Original language	English
Journal	Proceedings of the National Academy of Science of the United States of America
Volume	105
Issue number	17
Pages (from-to)	6398-6402
Number of pages	5
ISSN	0027-8424
DOIs	https://doi.org/10.1073/pnas.0802384105
Publication status	Published - 2008

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Critical role of a K+ channel in Plasmodium berghei transmission revealed by targeted gene disruption. / Ellekvist, Peter; Maciel, Jorge; Mlambo, Godfree et al.
In: Proceedings of the National Academy of Science of the United States of America, Vol. 105, No. 17, 2008, p. 6398-6402.

Research output: Contribution to journal › Journal article › Research › peer-review

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

abstract = "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.",

author = "Peter Ellekvist and Jorge Maciel and Godfree Mlambo and Ricke, {Christina H{\o}ier} and Hanne Colding and Klaerke, {Dan Arne} and Nirbhay Kumar",

note = "Keywords: Amino Acid Sequence; Animals; Anopheles; Gene Targeting; Kinetics; Life Cycle Stages; Malaria; Mice; Molecular Sequence Data; Parasites; Phenotype; Plasmodium berghei; Plasmodium falciparum; Potassium; Potassium Channels; Rubidium; Sequence Analysis, Protein; Sequence Homology, Amino Acid; Virulence",

year = "2008",

doi = "10.1073/pnas.0802384105",

language = "English",

volume = "105",

pages = "6398--6402",

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T1 - Critical role of a K+ channel in Plasmodium berghei transmission revealed by targeted gene disruption

AU - Ellekvist, Peter

AU - Maciel, Jorge

AU - Mlambo, Godfree

AU - Ricke, Christina Høier

AU - Colding, Hanne

AU - Klaerke, Dan Arne

AU - Kumar, Nirbhay

N1 - Keywords: Amino Acid Sequence; Animals; Anopheles; Gene Targeting; Kinetics; Life Cycle Stages; Malaria; Mice; Molecular Sequence Data; Parasites; Phenotype; Plasmodium berghei; Plasmodium falciparum; Potassium; Potassium Channels; Rubidium; Sequence Analysis, Protein; Sequence Homology, Amino Acid; Virulence

PY - 2008

Y1 - 2008

N2 - 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.

AB - 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.

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DO - 10.1073/pnas.0802384105

M3 - Journal article

C2 - 18434537

SN - 0027-8424

VL - 105

SP - 6398

EP - 6402

JO - Proceedings of the National Academy of Science of the United States of America

JF - Proceedings of the National Academy of Science of the United States of America

IS - 17

ER -

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

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