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Am J Physiol Cell Physiol (February 13, 2002). doi:10.1152/ajpcell.00504.2001
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Articles in PresS, published online ahead of print February 13, 2002
Am J Physiol Cell Physiol, 10.1152/ajpcell.00504.2001
Submitted on October 22, 2001
Accepted on February 6, 2002

The ClC-3 Chloride Channel Promotes Acidification of Lysosomes in CHO-K1 and Huh-7 Cells

Xinhua Li1, Ting Wang1, Zhifang Zhao1, and Steven A Weinman2*

1 Physiology and Biophysics, University of Texas Medical Branch, Galveston, TX, USA
2 Physiology and Biophysics, University of Texas Medical Branch, Galveston, TX, USA; Internal Medicine, University of Texas Medical Branch, Galveston, TX, USA

* To whom correspondence should be addressed. E-mail: sweinman{at}utmb.edu.

ClC-3 is a voltage-gated chloride channel that is highly conserved and widely expressed but its function, localization and properties are a matter of considerable debate. In this study we have shown that heterologous expression of ClC-3 in either CHO-K1 or 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 chloride channel activity. Manipulation of the intracellular chloride concentration demonstrated that the ClC-3 associated vesicles shrink and swell consistent with a highly chloride permeable membrane. The ClC-3 vesicles were identified as lysosomes based on their colocalization with the lysosomal associated proteins lamp-1, lamp-2, and cathepsin D, and failure to co-localize with fluorescently labeled endosomes. We conclude that ClC-3 is an intracellular channel that conducts chloride 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.




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