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100 1 _ |a Guzman, Raul
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245 _ _ |a Preferential Association with ClC-3 Permits Sorting of ClC-4 into Endosomal Compartments
260 _ _ |a Bethesda, Md.
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520 _ _ |a ClC-4 is an intracellular Cl--H+ exchanger, which is highly expressed in the brain and whose dysfunction has been linked to intellectual disability and epilepsy. We here studied the subcellular localization of human ClC-4 in heterologous expression systems. ClC-4 is retained in the endoplasmic reticulum (ER) upon overexpression in HEK293T cells. Co-expression with distinct ClC-3 splice variants targets ClC-4 to late endosome/lysosomes (ClC-3a and ClC-3b), recycling endosome (ClC-3c) or to the Golgi (ClC-3e). When expressed in cultured astroctyes ClC-4 sorts to endocytic compartments in WT cells, but was retained in the ER in Clcn3-/- cells. To understand the virtual absence of ER localized ClC-4 in WT cells we performed association studies by high resolution clear native gel electrophoresis (hrCNE). Whereas other CLCm channels and transporters form stable dimers, ClC-4 was mostly observed as monomer, with ClC-3-ClC-4 heterodimers being more stable than ClC-4 homodimers. We conclude that unique oligomerization properties of ClC-4 permits regulated targeting of ClC-4 to various endosomal compartments system via expression of different ClC-3 splice variants.
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700 1 _ |a Bungert, Stefanie
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700 1 _ |a Fahlke, Christoph
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