FIGURE 4: Regulation of ion transporter endocytosis by osmotic stress. Under iso-osmotic conditions NHE7 is continuously endocytosed via CME, thereby limiting its transport activity at the cell surface. Upon hyperosmotic conditions, endocytosis of NHE7 is downregulated resulting in elevated NHE7 surface levels. Increased NHE7 activity at the plasma membrane elevates Na⁺ influx, which via the Na⁺/Ca²⁺ exchanger NCX1 leads to increased intracellular Ca²⁺ levels and the Ca²⁺/Calcineurin-mediated dephosphorylation of the transcription factor TFEB to induce lysosomal and autophagy gene expression. The ensuing increased cellular degradative capacity is beneficial for counteracting protein aggregation caused by hyperosmotic conditions (see section ”Osmotic stress” for further details).