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1 Department of Physiology and Biophysics and 2 Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas 77555
ClC-3 is a voltage-gated Cl
channel that is highly conserved and widely expressed, although its
function, localization, and properties remain a matter of considerable
debate. In this study, we have shown that heterologous expression of
ClC-3 in either Chinese hamster ovary (CHO-K1) or human hepatoma
(Huh-7) cells results in the formation of large, acidic vesicular
structures within cells. Vesicle formation is prevented by bafilomycin,
an inhibitor of the vacuolar ATPase, and is not induced by an E224A mutant of ClC-3 with altered channel activity. This demonstrates that
vesicle formation requires both proton pumping and Cl
channel activity. Manipulation of the intracellular Cl
concentration demonstrated that the ClC-3-associated vesicles shrink
and swell consistent with a highly Cl-permeable membrane.
The ClC-3 vesicles were identified as lysosomes based on their
colocalization with the lysosome-associated proteins lamp-1, lamp-2,
and cathepsin D and on their failure to colocalize with fluorescently
labeled endosomes. We conclude that ClC-3 is an intracellular channel
that conducts Cl when it is present in intracellular
vesicles. Its overexpression results in its appearance in enlarged
lysosome-like structures where it contributes to acidification by
charge neutralization.
endosomes; bafilomycin; ClC channels
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