Specific inhibition of the plasmodial surface anion channel by dantrolene.
The plasmodial surface anion channel (PSAC), induced on human erythrocytes by the malaria parasite Plasmodium falciparum, is an important target for antimalarial drug development because it may contribute to parasite nutrient acquisition. However, known antagonists of this channel are quite nonspecific, inhibiting many other channels and carriers. This lack of specificity not only complicates drug development but also raises doubts about the exact role of PSAC in the well-known parasite-induced permeability changes. We recently identified a family of new PSAC antagonists structurally related to dantrolene, an antagonist of muscle Ca++ release channels. Here, we explored the mechanism of dantrolene's actions on parasite-induced permeability changes. We found that dantrolene inhibits the increased permeabilities of sorbitol, two amino acids, an organic cation, and hypoxanthine, suggesting a common pathway shared by these diverse solutes. It also produced parallel reductions in PSAC single-channel and whole-cell Cl- currents. In contrast to its effect on parasite-induced permeabilities, dantrolene had no measurable effect on five other classes of anion channels, allaying concerns of poor specificity inherent to other known antagonists. Our studies indicate that dantrolene binds PSAC at an extracellular site distinct from the pore, where it inhibits the conformational changes required for channel gating. Its affinity for this site depends on ionic strength, implicating electrostatic interactions in dantrolene binding. In addition to the potential therapeutic applications of its derivatives, dantrolene's specificity and its defined mechanism of action on PSAC make it a useful tool for transport studies of infected erythrocytes.
Lisk
Godfrey
G
Laboratory of Malaria and Vector Research, NIAID/NIH, Room 3W-01, 12735 Twinbrook Parkway, Rockville, Maryland 20852-8132, USA.
Kang
Myungsa
M
Cohn
Jamieson V
JV
Desai
Sanjay A
SA
D000818:Animals; D000838:Anions / Q000378:metabolism*; D000962:Antimalarials / Q000494:pharmacology; D002463:Cell Membrane Permeability; D002712:Chlorides / Q000378:metabolism; D003620:Dantrolene / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004910:Erythrocyte Membrane / Q000187:drug effects / Q000378:metabolism / Q000469:parasitology; D006801:Humans; D015640:Ion Channel Gating; D007473:Ion Channels / Q000378:metabolism*; D015394:Molecular Structure; D009125:Muscle Relaxants, Central / Q000737:chemistry / Q000494:pharmacology; D009865:Oocytes / Q000502:physiology; D009996:Osmotic Fragility; D018408:Patch-Clamp Techniques; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000378:metabolism*; D013012:Sorbitol / Q000378:metabolism; D014982:Xenopus laevis
D000838:Anions; D000962:Antimalarials; D002712:Chlorides; D007473:Ion Channels; D009125:Muscle Relaxants, Central; D013012:Sorbitol; D003620:Dantrolene