The principle anion channel on P. falciparum ‐infected human erythrocytes is likely parasite‐encoded

Abstract

The plasmodial surface anion channel (PSAC) is a voltage-dependent anion channel on the surface of human erythrocytes infected with Plasmodium falciparum. Electrophysiological studies from other groups suggest that the parasite may also induce additional ion channels, raising two important questions. First, which of these ion channels are responsible for parasite-induced increases in the permeabilities of needed solutes such as sugars, amino acids, purines, and organic cations? Second, does the uptake result from a parasite-encoded ion channel or does it result from modifications to host proteins? Here, we show that the parasite-induced permeabilities of two organic solutes, sorbitol and lactate, are inhibited by furosemide with a dose response precisely matching that for inhibition of PSAC-mediated currents, as detected with single molecule and whole-cell patch-clamp. PSAC activity was not affected by biochemical manipulations or by changes in host genetic factors such as a key CFTR mutation. We then explored PSAC’s origin with two geographically divergent parasite isolates cultured in human erythrocytes from the same donors. There were significant differences in the voltage-dependent gating behavior of PSAC that correlated with the parasite isolate used, but not with host genetic factors. PSAC also exhibits a unique pharmacological profile. Finally, unlike other anion channels, PSAC exhibits an unusual type of voltage-dependent inactivation that may be important for its function. Our findings suggest that PSAC is a parasite-encoded ion channel predominantly responsible for uptake of needed organic solutes and for removal of parasite metabolic waste products. PSAC’s unique functional and pharmacological properties implicate it as a novel target for antimalarial drug development.