The Intracellular Na+/H+ Exchanger NHE7 Effects a Na+-Coupled, but Not K+-Coupled Proton-Loading Mechanism in Endocytosis

Vesicular H+-ATPases and ClC-chloride transporters are described to acidify intracellular compartments, which also express the highly conserved Na+/H+ exchangers NHE6, NHE7, and NHE9. Mutations of these exchangers cause autism-spectrum disorders and neurodegeneration. NHE6, NHE7, and NHE9 are hypothesized to exchange cytosolic K+ for H+ and alkalinize vesicles, but this notion has remained untested in K+ because their intracellular localization prevents functional measurements. Using proton-killing techniques, we selected a cell line that expresses wild-type NHE7 at the plasma membrane, enabling measurement of the exchanger’s transport parameters. We found that NHE7 transports Li+ and Na+, but not K+, is nonreversible in physiological conditions and is constitutively activated by cytosolic H+. Therefore, NHE7 acts as a proton-loading transporter rather than a proton leak. NHE7 mediates an acidification of intracellular vesicles that is additive to that of V-ATPases and that accelerates endocytosis. This study reveals an unexpected function for vesicular Na+/H+ exchangers and provides clues for understanding NHE-linked neurological disorders. [Display omitted] •NHE7 is not a proton leak but instead is an acidifier of intracellular compartments•NHE7-mediated vesicular acidification accelerates endocytosis•NHE7 features provide clues for autism-spectrum-related diseases and lithium action The acidification of intracellular compartments is critical for a wide range of processes, such as protein maturation and degradation, receptor recycling and desensitization, and neurotransmitter loading into synaptic vesicles. Milosavljevic et al. report that the highly conserved intracellular Na+/H+ exchanger NHE7 is an acidifier of intracellular compartments that displays prominent expression in large integrative neurons. These findings provide new clues for understanding NHE7 cerebral functions and the links between its mutations and neurological disorders.