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Vol. 20, Issue 13, 3125-3141, July 1, 2009

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Revisiting the Role of Cystic Fibrosis Transmembrane Conductance Regulator and Counterion Permeability in the pH Regulation of Endocytic Organelles

Herve Barriere^*, Miklos Bagdany^*, Florian Bossard^*, Tsukasa Okiyoneda^*, Gabriella Wojewodka, Dieter Gruenert, Danuta Radzioch, and Gergely L. Lukacs^*

*Department of Physiology, McGill University, Montreal, Quebec, H3G 1Y6, Canada; Research Institute of the McGill University Health Center, Montreal, Quebec, H3G 1A4 Canada; and Research Institute, California Pacific Medical Center, San Francisco, CA 94107

Submitted January 21, 2009; Revised April 10, 2009; Accepted April 27, 2009
Monitoring Editor: Sandra L. Schmid

Organellar acidification by the electrogenic vacuolar proton-ATPase is coupled to anion uptake and cation efflux to preserve electroneutrality. The defective organellar pH regulation, caused by impaired counterion conductance of the mutant cystic fibrosis transmembrane conductance regulator (CFTR), remains highly controversial in epithelia and macrophages. Restricting the pH-sensitive probe to CFTR-containing vesicles, the counterion and proton permeability, and the luminal pH of endosomes were measured in various cells, including genetically matched CF and non-CF human respiratory epithelia, as well as cftr^+/+ and cftr^–/– mouse alveolar macrophages. Passive proton and relative counterion permeabilities, determinants of endosomal, lysosomal, and phagosomal pH-regulation, were probed with FITC-conjugated transferrin, dextran, and Pseudomonas aeruginosa, respectively. Although CFTR function could be documented in recycling endosomes and immature phagosomes, neither channel activation nor inhibition influenced the pH in any of these organelles. CFTR heterologous overexpression also failed to alter endocytic organellar pH. We propose that the relatively large CFTR-independent counterion and small passive proton permeability ensure efficient shunting of the proton-ATPase–generated membrane potential. These results have implications in the regulation of organelle acidification in general and demonstrate that perturbations of the endolysosomal organelles pH homeostasis cannot be linked to the etiology of the CF lung disease.

Address correspondence to: Gergely L. Lukacs (gergely.lukacs{at}mcgill.ca)

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