FIGURE 1.

Na⁺ reabsorption in the distal convoluted tubule. Schematic overview of a distal convoluted tubule cell indicating all genes and proteins that have been associated with Gitelman syndrome. Na⁺ enters the cell at the luminal membrane via the Na⁺-Cl⁻ co-transporter (NCC). At the basolateral membrane, Na⁺ is extruded from the cell by the Na⁺-K⁺ ATPase. The ATP production required for Na⁺-K⁺ ATPase activity is dependent on mitochondrial function. Basolateral recycling of K⁺ via Kir4.1/Kir5.1 channels is essential to drive the Na⁺-K⁺ ATPase and Cl-extrusion via ClC-Kb Cl⁻ channels. Low intracellular Cl⁻ concentrations activate an intracellular signalling cascade of WNK and SPAK kinases, which results in phosphorylation of NCC.