Fig. 2.

Schematic model of the effect of NaCl cotransporter (NCC) activity on distal convoluted tubule (DCT) Mg²⁺ handling. A: NCC inactivation reduces early DCT (DCT1) mass and Na⁺-K⁺-ATPase activity, leading to hypomagnesemia. This is caused by decreased Mg²⁺ entry through transient receptor potential channel subfamily M member 6 (TRPM6). B: NCC activation increases DCT mass, but TRPM6 per unit DCT1 mass is downregulated, resulting in a minimal effect on Mg²⁺ entry. C: Na⁺-K⁺-ATPase activity is a central determinant of DCT Mg²⁺ reabsorption because it provides the driving force for Mg²⁺ entry via TRPM6. Hepatocyte nuclear factor-1β (HNF1B) plays a key role in Mg²⁺ handling, since it promotes transcription of Na⁺-K⁺-ATPase subunit-γ (FXYD2) and Kir5.1, which enhance Na⁺-K⁺-ATPase activity. Kir4.1/Kir5.1 activity is closely related to NCC activity. D: Mg²⁺ deficiency may promote NCC degradation via ubiquitin ligase neuronal precursor cell developmentally downregulated 4-2 (NEDD4-2). Increased Na⁺ delivery to downstream segments can promote K⁺ secretion. Mg²⁺ deficiency upregulates TRPM6 expression, which enhances Mg²⁺ entry, but NCC downregulation can cause DCT1 atrophy. Combined with reduced levels of the intracellular Mg²⁺ concentration ([Mg²⁺]_i) for Na⁺-K⁺-ATPase activity, this would be expected to reduce Mg²⁺ entry via TRPM6 channels.