Critical role of a K+ channel in Plasmodium berghei transmission revealed by targeted gene disruption.
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.
Ellekvist
Peter
P
Department of Cellular and Molecular Medicine, Faculty of Health Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark.
Maciel
Jorge
J
Mlambo
Godfree
G
Ricke
Christina H
CH
Colding
Hanne
H
Klaerke
Dan A
DA
Kumar
Nirbhay
N
D000595:Amino Acid Sequence; D000818:Animals; D000852:Anopheles / Q000469:parasitology; D018390:Gene Targeting; D007700:Kinetics; D008018:Life Cycle Stages; D008288:Malaria / Q000469:parasitology / Q000635:transmission*; D051379:Mice; D008969:Molecular Sequence Data; D010271:Parasites / Q000235:genetics / Q000254:growth & development / Q000472:pathogenicity; D010641:Phenotype; D010962:Plasmodium berghei / Q000235:genetics* / Q000254:growth & development / Q000472:pathogenicity; D010963:Plasmodium falciparum; D011188:Potassium / Q000378:metabolism; D015221:Potassium Channels / Q000737:chemistry / Q000235:genetics*; D012413:Rubidium / Q000378:metabolism; D020539:Sequence Analysis, Protein; D017386:Sequence Homology, Amino Acid; D014774:Virulence
D015221:Potassium Channels; D012413:Rubidium; D011188:Potassium