Figure 2.

Transcellular Mg²⁺ reabsorption along the DCT. (A) Mg²⁺ enters cells along the early (DCT1) and late DCT (DCT2) through TRPM6, which requires interaction with TRPM7 for maximum activity. The basolateral exit pathway remains to be identified, but candidates are shown. Because transport through NCC is electroneutral, the potassium channel Kv1.1 is believed to generate the drive for Mg²⁺ entry at the apical membrane. NCC is activated by phosphorylation via the WNK-SPAK kinase pathway. WNK kinases are inhibited by direct binding of Cl⁻; coupling of K⁺ and Cl⁻ efflux via Kir4.1/5.1 and CLC-KB as a result of increased plasma [K⁺] lowers intracellular [Cl⁻] leading to WNK kinase activation. Energy consumption by the basolateral Na⁺-K⁺-ATPase drives all of these processes (see Figure 3). (B) Activation of EGFR induces TRPM6 mRNA expression and activity, and calcineurin may promote this. UMOD may stimulate TRPM6 activity by inhibiting its endocytosis. (C) ARL15, a GTP-binding protein, may activate TRPM6 but inhibit cyclin and CNNMs.