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© The Rockefeller University Press, 0021-9525/1998//335 $5.00
The Journal of Cell Biology, Volume 140, Number 2, , 1998 335-345

Article

Differential Stimulation of the Na+/H+ Exchanger Determines Chloroquine Uptake in Plasmodium falciparum



Stefan Wünsch*, Cecilia P. Sanchez*, Michael Gekle{ddagger}, Lars Große-Wortmann*, Jochen Wiesner*, and Michael Lanzer*

* Zentrum für Infektionsforschung, {ddagger} Institut für Physiologie der Universität Würzburg, D-97070 Würzburg, Germany

Here we describe the identification and characterization of a physiological marker that is associated with the chloroquine-resistant (CQR) phenotype in the human malarial parasite Plasmodium falciparum. Single cell in vivo pH measurements revealed that CQR parasites consistently have an elevated cytoplasmic pH compared to that of chloroquine-sensitive (CQS) parasites because of a constitutively activated Na+/H+ exchanger (NHE). Together, biochemical and physiological data suggest that chloroquine activates the plasmodial NHE of CQS parasites, resulting in a transitory phase of rapid sodium/hydrogen ion exchange during which chloroquine is taken up by this protein. The constitutively stimulated NHE of CQR parasites are capable of little or no further activation by chloroquine. We propose that the inability of chloroquine to stimulate its own uptake through the constitutively activated NHE of resistant parasites constitutes a minimal and necessary event in the generation of the chloroquine-resistant phenotype.

Abbreviations used in this paper: βi, intracellular buffer capacity; BCECF-AM, fluorochromo 2'7'-bis-(2-carboxyethyl)-5,6-carboxyfluorescein acetomethyl ester; CQR, chloroquine resistant; EIPA, 5-(N-ethyl- N-isopropyl)amiloride; CQS, chloroquine sensitive; HMA, 5-N(N-hexamethylene)amiloride; IC50, 50% inhibitory concentration; pHi, intracellular pH; NHE, Na+/H+ exchanger; SBFI, sodium-binding benzofuran isophthalate-acetoxymethylester.

Address all correspondence to Michael Lanzer, Zentrum für Infektionsforschung, Universität Würzburg, Röntgenring 11, D-97070 Würzburg, Germany. Tel.: (49) 93-13-12-151. Fax: (49) 93-13-12-578.


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