Abstract
ClC-2 is a ubiquitously expressed plasma membrane Cl - channel that reportedly controls the ionic environment in mouse retina and testis. Beyond that, ClC-2 might sense cellular energy status and cellular stress by its carboxy- terminal cystathionine-beta-synthase (CBS) domains and by its molecular interaction with the heat shock protein Hsp90, respectively. In mature human and mouse erythrocytes, ClC-2 is activated by oxidative stress and by malaria infection. This article describes possible function of erythrocyte ClC-2 channels for the programmed death of oxidatively injured erythrocytes and for the regulatory volume decrease of malaria-infected erythrocytes.
Highlights
ClC-2 is a ubiquitously expressed plasma membrane Cl- channel that reportedly controls the ionic environment in mouse retina and testis
Circumstantial evidence for a parasite-derived origin of the PLASMODIUM FALCIPARUM-ENCODED ERYTHROCYTE SURFACE ANION CHANNEL (PSAC) came from the observations that i) PSAC is functionally conserved in divergent malaria parasites [68], ii) two distinct parasite isolates, grown in erythrocytes from a single donor, exhibit channel activity with measurably different voltage-dependent gating [69], iii) a mutation in P. falciparum conferring blasticidin S-resistance was linked to altered gating, pharmacology, selectivity profile or occurrence of sub-conductance states of the PSAC channel in single channel recording [70] iv) changes in PSAC reduce leupeptin uptake and can confer drug resistance in infected erythrocytes [71]
Volume stress-associated activity, zinc sensitivity, relative furosemide and nitro-2-(3-phenylpropylamino)-benzoic acid (NPPB)-insensitivity, inward rectification and very low single channel conductance, is highly reminiscent to ClC-2, strongly suggesting that the PSAC phenomenon is generated by ClC-2 channels and further suggesting that ClC-2 is not involved in the NPPB- and furosemide-sensitive organic osmolyte permeability of P. falciparum-infected erythrocytes
Summary
ClC-2 is a ubiquitously expressed plasma membrane Cl- channel that reportedly controls the ionic environment in mouse retina and testis. Stress-induced loss of KCl, cell shrinkage and execution of the suicidal erythrocyte death program is attenuated by anion channel inhibitors. ACTIVATION AND FUNCTIONAL SIGNIFICANCE OF CLC-2 CHANNELS IN MALARIA-INFECTED ERYTHROCYTES
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