Transport of diverse substrates into malaria-infected erythrocytes via a pathway showing functional characteristics of a chloride channel.

Abstract

Following infection by the malaria parasite, Plasmodium falciparum, human erythrocytes show increased permeability to a variety of low molecular weight solutes. In this study a number of anion transport blockers were identified as potent inhibitors of the transport of a wide range of solutes into human erythrocytes infected in vitro with P. falciparum. 5-Nitro-2-(3-phenyl-propylamino)benzoic acid (NPPB), furosemide, and niflumate blocked the malaria-induced transport of monovalent cations, neutral amino acids, sugars, nucleosides, and monovalent anions. For all of the substrates tested the order of potency of these three inhibitors was the same (NPPB > furosemide > niflumate) and dose-response curves for the effect of these inhibitors on malaria-induced choline transport were similar to those for malaria-induced thymidine transport. The data suggest that much, if not all, of the high capacity (non-saturable) transport of low molecular weight solutes into P. falciparum-infected erythrocytes is via a single type of pathway. The broad specificity of the pathway, its non-saturability in the physiological concentration range, and its failure to distinguish between stereoisomers (L- and D-alanine) are consistent with its being a type of pore or channel. For those substrates for which quantitative influx measurements were made the magnitude of the malaria-induced (inhibitor-sensitive) transport was in the order: Cl- > lactate > thymidine, adenosine > carnitine > choline > K+. The pathway is therefore anion-selective. The pharmacological and substrate-selectivity properties of the pathway show marked similarities to those of chloride channels in other cell types; this raises the possibility that the high capacity transport of small organic solutes may be an important and, as yet, largely unrecognized role for such channels in other tissues.