Is the Putative Chloroquine Resistance Mediator CG2 the Na+/H+ Exchanger of Plasmodium falciparum?

Letter to the Editor lower affinity for chloroquine and a reduced transport Is the Putative Chloroquine rate. Moreover, their NHE is in a constitutively activated Resistance Mediator CG2 the state, rendering this protein incapable of importing chlo-roquine since no further activation by chloroquine is possible (Wü nsch et al., 1998). of Plasmodium falciparum? Given that complex polymorphisms within cg2 as well as changes in the biochemical and physiological proper-The genesis of chloroquine-resistant Plasmodium falci-ties of the PfNHE are all genetically linked with the CQR parum, which has severely complicated the clinical man-phenotype, this begs the question: Is CG2 the P. falci-agement of tropical malaria, has been the focus of in-parum NHE? CG2, however, does not share obvious tense scientific investigation since it first emerged about homologies with any known NHE. This is not surprising 40 years ago. Although several models have been pro-since physiological data suggest that the PfNHE is not posed to explain the chloroquine-resistant (CQR) phe-a classical electroneutral NHE, as found in higher eu-notype (Krogstad et al., 1987; Ginsburg and Stein, 1991; karyotes, but rather an electrogenic amiloride-sensitive Martiney et al., 1995), the mechanism, as well as the NHE, reminiscent of those found in invertebrates. As genetic determinant(s), has remained elusive. Using a no electrogenic NHE has thus far been cloned, a stan-genetic approach, a 400 kb region of the P. falciparum dard homology search would not have revealed CG2's chromosome 7 was found to segregate with the CQR identity. phenotype (Wellems et al., 1991). Fine scale analysis of A closer look at CG2, however, reveals certain struc-this locus has recently identified a promising candidate tural and functional features we would expect to find in gene, cg2, of hitherto undefined function, encoding a the PfNHE, including a consensus amiloride-binding site ‫033ف‬ kDa transmembrane protein located at both the and a region homologous to a sodium/hydrogen ion parasite plasma membrane and the food vacuole (Su et transport domain of eukaryotic NHEs (Figures 1 and 2). al., 1997). The locations of these sites are spatially conserved and We have recently shown that chloroquine is taken up, lie at appropriate regions of CG2 predicted with high and concentrated by, the action of the P. falciparum probability to be transmembrane domains, of which CG2 sodium/hydrogen ion exchanger (PfNHE) (Sanchez et contains 10–12 typical of NHEs (Figure 1). CG2's size al., 1997; Wü nsch et al., 1998), a plasma membrane– and cellular location …