Malaria parasite mutants with altered erythrocyte permeability: a new drug resistance mechanism and important molecular tool

Erythrocytes infected with plasmodia, including those that cause human malaria, have increased permeability to a diverse collection of organic and inorganic solutes. While these increases have been known for decades, their mechanistic basis was unclear until electrophysiological studies revealed flux through one or more ion channels on the infected erythrocyte membrane. Current debates have centered on the number of distinct ion channels, which channels mediate the transport of each solute and whether the channels represent parasite-encoded proteins or human channels activated after infection. This article reviews the identification of the plasmodial surface anion channel and other proposed channels with an emphasis on two distinct channel mutants generated through in vitro selection. These mutants implicate parasite genetic elements in the parasite-induced permeability, reveal an important new antimalarial drug resistance mechanism and provide tools for molecular studies. We also critically examine the technical issues relevant to the detection of ion channels by electrophysiological methods; these technical considerations have general applicability for interpreting studies of various ion channels proposed for the infected erythrocyte membrane.