Caveolins bind to (Na+, K+)/H+ exchanger NHE7 by a novel binding module.

NHE7 was identified as the first mammalian organelle-membrane type (Na+, K+)/H+ exchanger that may contribute to the ion homeostasis in the trans-Golgi network (TGN) and endosomes. Here we show that caveolins directly bind to the C-terminal extension of NHE7 by an unconventional binding-module. NHE7 is partly associated with caveolae/lipid raft fractions, and heterologous expression of caveolin dominant-negative mutants as well as cholesterol depriving drugs diminished such associations. In contrast to the wild type NHE7, a deletion mutant lacking the C-terminal extension was predominantly detected in non-caveolae/lipid rafts. We further show that a small fraction of NHE7 is targeted to the cell surface and subsequently internalized. Endocytosis of NHE7 was efficiently inhibited by pharmacological maneuvers that block clathrin-dependent endocytosis, whereas dominant-negative caveolin mutants or methyl beta-cyclodextrin did not affect NHE7-internalization. Thus, NHE7 associates with both caveolae/lipid rafts and non-caveolae/lipid raft, and the two pools likely exhibit separate dynamics.