Fig. 10. Working model of the role of polyvalent anions in hepatopancreatic lysosomal heavy metal sequestration and detoxification. Membrane-bound, ATP-dependent, V-ATPase (Protein 1) transfers protons into the vesicle interior, creating a decrease in pH, an accumulation of hydrogen ions, and an inside-positive membrane potential. The outwardly directed proton gradient and positive vesicular interior provide the driving force for the asymmetric exchange of cytosolic divalent metals for intravesicular hydrogen ions by an ATP-dependent Zn²⁺-ATPase, or a 3H⁺/1Zn²⁺ exchanger (Protein 2). Polyvalent cytosolic anions such as sulfate^2– or phosphate^3– exchange with intravesicular monovalent anions such as Cl^– or OH^– by a second asymmetric antiporter (Protein 3), which uses the membrane potential as a driving force for exchange. Both divalent metals and polyvalent anions increase in concentration inside vesicles at acidic pH and are retained because they cannot be accommodated on the intravesicular binding sites of the exchangers. Divalent metals and polyvalent anions form precipitates (concretions) as the V-ATPase decreases in activity and the intravesicular pH rises.