Abstract
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.
Highlights
Plasmodium falciparum is metabolically highly active and depends on ample supply of nutrients [1]
The present observations provide conclusive evidence for expression of ClC-2 channels in red blood cell (RBC) and show that the channels are activated by oxidation and by infection with Plasmodium
The present study confirms the participation of host cell membrane proteins in the altered permeability of infected erythrocytes
Summary
Plasmodium falciparum is metabolically highly active and depends on ample supply of nutrients [1]. Tracer flux and isosmotic hemolysis experiments characterize the transport systems activated by the parasite as organic osmolyte and anion channels (with additional low but significant cation permeability) [1, 10] similar to those mediating regulatory volume decrease in many nucleated cells [11]. Recent whole cell patch clamp recordings revealed inwardly rectifying [13,14,15,16] and outwardly rectifying anion channels [14, 17, 18] as well as nonselective cation channels [19] in the cell membrane of infected erythrocytes confirming that more than one channel type contributes to the enhanced erythrocyte permeability.
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