1. There are no effective ways of screening for potential modulators of volume-regulated
anion channels in their native cell type. Generally, cell lines are used for this purpose. Using HeLa and C6
glioma cells, we identified the
pyrethroids as a novel class of compounds that inhibit
taurine efflux through volume-regulated
anion transport pathways in these cells. Subsequently, we examined their effects on volume-regulated
anion channels in guinea-pig ventricular myocytes to determine whether results obtained using cell lines could be extrapolated to other tissues. 2.
Tetramethrin inhibited
taurine efflux in both HeLa and C6
glioma cells with Ki values of approximately 26 and 16 micro mol/L, respectively.
Bioallethrin and
fenpropathrin inhibited volume-sensitive
taurine efflux from C6
glioma cells, but not from HeLa cells. The Ki values for
bioallethrin and
fenpropathrin were 70 and 59 micro mol/L, respectively. 3. Volume-sensitive I- efflux was observed in HeLa cells but not in C6
glioma cells, suggesting that the
taurine efflux pathway in C6
glioma cells may be different to that of the I- efflux pathway.
Cyfluthrin,
tetramethrin,
fenpropathrin,
tefluthrin and
bioallethrin all significantly inhibited volume-sensitive I- efflux from HeLa cells at 100 micro mol/L. 4. Patch-clamp experiments have shown inhibition of ICl,vol in guinea-pig ventricular myocytes by
fenpropathrin, but not
tetramethrin or
cypermethrin, at 100 micro mol/L. This revealed that further differences exist between ICl,vol in guinea-pig ventricular myocytes and the
anion transport pathways in C6
glioma and HeLa cells. 5. In conclusion, we have shown that
pyrethroids differentially inhibit volume-regulated
anion and
taurine efflux in a number of cell types. Because these compounds have different effects in different cells, it is likely that: (i) more than one pathway is involved in the volume-sensitive transport of
anions and organic osmolytes; and (ii) the molecular identities of the channels underlying
anion transport are different. Finally, for the reasons given above, care should be taken when extrapolating data from one cell type to another. However, in the absence of an existing high-throughput screen,
taurine efflux still represents a viable route for the identification of potential modulators of volume-regulated
ion channels.