FIGURE 4.

Molecular pathways involved in the effects of a high K⁺ diet on the NCC. High extracellular K⁺ concentration is sensed by K⁺ channel Kir4.1/5.1 and causes membrane depolarization. This may lead to an increase in intracellular calcium (Ca²⁺) through unknown mechanisms. Ca²⁺ stimulates calcium-binding protein calmodulin (CaM) and downstream PPs such as PP3 (calcineurin). This dephosphorylates NCC. In acute K⁺ loading, mechanisms that depend on intracellular chloride ([Cl⁻]_in) may also be stimulated through effects dependent on the K⁺ channel Kir4.1/5.1. An increase in [Cl⁻]_in may inhibit WNK4 autophosphorylation. This would prevent SPAK–OSR1 phosphorylation and ultimately, NCC phosphorylation.