title: A model of lysosomal pH regulation.
abstract: Lysosomes must maintain an acidic luminal pH to activate hydrolytic enzymes and degrade internalized macromolecules. Acidification requires the vacuolar-type H(+)-ATPase to pump protons into the lumen and a counterion flux to neutralize the membrane potential created by proton accumulation. Early experiments suggested that the counterion was chloride, and more recently a pathway consistent with the ClC-7 Cl(-)/H(+) antiporter was identified. However, reports that the steady-state luminal pH is unaffected in ClC-7 knockout mice raise questions regarding the identity of the carrier and the counterion. Here, we measure the current-voltage characteristics of a mammalian ClC-7 antiporter, and we use its transport properties, together with other key ion regulating elements, to construct a mathematical model of lysosomal pH regulation. We show that results of in vitro lysosome experiments can only be explained by the presence of ClC-7, and that ClC-7 promotes greater acidification than Cl(-), K(+), or Na(+) channels. Our models predict strikingly different lysosomal K(+) dynamics depending on the major counterion pathways. However, given the lack of experimental data concerning acidification in vivo, the model cannot definitively rule out any given mechanism, but the model does provide concrete predictions for additional experiments that would clarify the identity of the counterion and its carrier.
authors.affiliation: Department of History and Philosophy of Science, University of Pittsburgh, Pittsburgh, PA 15260, USA.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Ishida
authors.forename: Smita
authors.initials: S
authors.lastname: Nayak
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Mindell
authors.forename: Michael
authors.initials: M
authors.lastname: Grabe
mesh_terms: D000200:Action Potentials; D018118:Chloride Channels / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008247:Lysosomes / Q000378:metabolism*; D008954:Models, Biological; D009154:Mutation; D011188:Potassium / Q000378:metabolism; D011522:Protons
chemical_list: C097540:CLCN7 protein, human; D018118:Chloride Channels; D011522:Protons; D011188:Potassium