© The Rockefeller University Press,
0021-9525/1998//335 $5.00
The Journal of Cell Biology, Volume 140, Number 2,
, 1998 335-345
Differential Stimulation of the Na+/H+ Exchanger Determines Chloroquine Uptake in Plasmodium falciparum
Stefan Wünsch*,
Cecilia P. Sanchez*,
Michael Gekle
,
Lars Große-Wortmann*,
Jochen Wiesner*, and
Michael Lanzer*
* Zentrum für Infektionsforschung,
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.

CiteULike
Complore
Connotea
Del.icio.us
Digg
Facebook
Reddit
Technorati
Twitter What's this?
This article has been cited by other articles:
-
Spry, C., Saliba, K. J.
(2009). The Human Malaria Parasite Plasmodium falciparum Is Not Dependent on Host Coenzyme A Biosynthesis. J. Biol. Chem.
284: 24904-24913
[Abstract]
[Full Text]
-
Rohrbach, P., Friedrich, O., Hentschel, J., Plattner, H., Fink, R. H. A., Lanzer, M.
(2005). Quantitative Calcium Measurements in Subcellular Compartments of Plasmodium falciparum-infected Erythrocytes. J. Biol. Chem.
280: 27960-27969
[Abstract]
[Full Text]
-
Naude, B., Brzostowski, J. A., Kimmel, A. R., Wellems, T. E.
(2005). Dictyostelium discoideum Expresses a Malaria Chloroquine Resistance Mechanism upon Transfection with Mutant, but Not Wild-type, Plasmodium falciparum Transporter PfCRT. J. Biol. Chem.
280: 25596-25603
[Abstract]
[Full Text]
-
Nyalwidhe, J., Baumeister, S., Hibbs, A. R., Tawill, S., Papakrivos, J., Volker, U., Lingelbach, K.
(2002). A Nonpermeant Biotin Derivative Gains Access to the Parasitophorous Vacuole in Plasmodium falciparum-infected Erythrocytes Permeabilized with Streptolysin O. J. Biol. Chem.
277: 40005-40011
[Abstract]
[Full Text]
-
Wissing, F., Sanchez, C. P., Rohrbach, P., Ricken, S., Lanzer, M.
(2002). Illumination of the Malaria Parasite Plasmodium falciparum Alters Intracellular pH. IMPLICATIONS FOR LIVE CELL IMAGING. J. Biol. Chem.
277: 37747-37755
[Abstract]
[Full Text]
-
Mehlotra, R. K., Fujioka, H., Roepe, P. D., Janneh, O., Ursos, L. M. B., Jacobs-Lorena, V., McNamara, D. T., Bockarie, M. J., Kazura, J. W., Kyle, D. E., Fidock, D. A., Zimmerman, P. A.
(2001). Evolution of a unique Plasmodium falciparum chloroquine-resistance phenotype in association with pfcrt polymorphism in Papua New Guinea and South America. Proc. Natl. Acad. Sci. USA
98: 12689-12694
[Abstract]
[Full Text]
-
Kirk, K.
(2001). Membrane Transport in the Malaria-Infected Erythrocyte. Physiol. Rev.
81: 495-537
[Abstract]
[Full Text]
-
Tiffert, T., Staines, H. M, Ellory, J C., Lew, V. L
(2000). Functional state of the plasma membrane Ca2+ pump in Plasmodium falciparum-infected human red blood cells. J. Physiol.
525: 125-134
[Abstract]
[Full Text]
-
Saliba, K. J., Kirk, K.
(1999). pH Regulation in the Intracellular Malaria Parasite, Plasmodium falciparum. H+ EXTRUSION VIA A V-TYPE H+-ATPase. J. Biol. Chem.
274: 33213-33219
[Abstract]
[Full Text]
-
Bray, P. G., Janneh, O., Raynes, K. J., Mungthin, M., Ginsburg, H., Ward, S. A.
(1999). Cellular Uptake of Chloroquine Is Dependent on Binding to Ferriprotoporphyrin IX and Is Independent of NHE Activity in Plasmodium falciparum. JCB
145: 363-376
[Abstract]
[Full Text]
-
Bray, P. G., Mungthin, M., Ridley, R. G., Ward, S. A.
(1998). Access to Hematin: The Basis of Chloroquine Resistance. Mol. Pharmacol.
54: 170-179
[Abstract]
[Full Text]
-
Hayashi, M., Yamada, H., Mitamura, T., Horii, T., Yamamoto, A., Moriyama, Y.
(2000). Vacuolar H+-ATPase Localized in Plasma Membranes of Malaria Parasite Cells, Plasmodium falciparum, Is Involved in Regional Acidification of Parasitized Erythrocytes. J. Biol. Chem.
275: 34353-34358
[Abstract]
[Full Text]
-
Saliba, K. J., Kirk, K.
(2001). H+-coupled Pantothenate Transport in the Intracellular Malaria Parasite. J. Biol. Chem.
276: 18115-18121
[Abstract]
[Full Text]