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. 2021 Mar 15;320(5):F719–F733. doi: 10.1152/ajprenal.00459.2020

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Published by the American Physiological Society

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Figure 8. — Simplified NaCl cotransporter (NCC) kinase and phosphatase cascade. A low intracellular Cl⁻ environment, induced by low extracellular K⁺ concentration, activates with-no-lysine kinase 4 (WNK4) and vice versa. Activated WNK4 binds to and phosphorylates STE20/SPS1-related proline-alanine-rich protein kinase (SPAK). Activated SPAK binds to and phosphorylates NCC, thereby increasing its activity. Protein phosphatase (PP)1 can remove activating phosphates from both SPAK and NCC. PP1 Inhibitor 1 (I-1), which is activated by protein kinase A (PKA), suppresses PP1 activity (30). I-1, the inhibitor, is dephosphorylated by PP3 (calcineurin) (35), suggesting a mechanism for the effects of tacrolimus on NCC.