Plasmodium induces swelling-activated ClC-2 anion channels in the host erythrocyte.
Intraerythrocytic growth of the human malaria parasite Plasmodium falciparum depends on delivery of nutrients. Moreover, infection challenges cell volume constancy of the host erythrocyte requiring enhanced activity of cell volume regulatory mechanisms. Patch clamp recording demonstrated inwardly and outwardly rectifying anion channels in infected but not in control erythrocytes. The molecular identity of those channels remained elusive. We show here for one channel type that voltage dependence, cell volume sensitivity, and activation by oxidation are identical to ClC-2. Moreover, Western blots and FACS analysis showed protein and functional ClC-2 expression in human erythrocytes and erythrocytes from wild type (Clcn2(+/+)) but not from Clcn2(-/-) mice. Finally, patch clamp recording revealed activation of volume-sensitive inwardly rectifying channels in Plasmodium berghei-infected Clcn2(+/+) but not Clcn2(-/-) erythrocytes. Erythrocytes from infected mice of both genotypes differed in cell volume and inhibition of ClC-2 by ZnCl(2) (1 mm) induced an increase of cell volume only in parasitized Clcn2(+/+) erythrocytes. Lack of ClC-2 did not inhibit P. berghei development in vivo nor substantially affect the mortality of infected mice. In conclusion, activation of host ClC-2 channels participates in the altered permeability of Plasmodium-infected erythrocytes but is not required for intraerythrocytic parasite survival.
Huber
Stephan M
SM
Departments of Physiology and Parasitology, Institute of Tropical Medicine, University of Tübingen, 72076 Germany. stephan.huber@uni-tuebingen.de
Duranton
Christophe
C
Henke
Guido
G
Van De Sand
Claudia
C
Heussler
Volker
V
Shumilina
Ekaterina
E
Sandu
Ciprian D
CD
Tanneur
Valerie
V
Brand
Verena
V
Kasinathan
Ravi S
RS
Lang
Karl S
KS
Kremsner
Peter G
PG
Hübner
Christian A
CA
Rust
Marco B
MB
Dedek
Karin
K
Jentsch
Thomas J
TJ
Lang
Florian
F
D000818:Animals; D000090007:CLC-2 Chloride Channels; D002463:Cell Membrane Permeability; D048429:Cell Size; D018118:Chloride Channels / Q000096:biosynthesis* / Q000378:metabolism; D004912:Erythrocytes / Q000166:cytology / Q000378:metabolism / Q000469:parasitology*; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009995:Osmosis; D018408:Patch-Clamp Techniques; D010962:Plasmodium berghei / Q000254:growth & development / Q000502:physiology*
D000090007:CLC-2 Chloride Channels; D018118:Chloride Channels; C000715428:Clcn2 protein, mouse