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

TY - JOUR

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.

U2 - 10.1073/pnas.0802384105

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 Sciences of the United States of America

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

IS - 17

ER -