Figure 9.

Regulation of NCC phosphorylation under different K⁺ conditions. Cullins are a family of E3 ligases that are activated through neddylation, a post-translational modification in which the ubiquitin-like modifier NEDD8 is covalently attached to the target protein. Active cullin complexes can bind to their substrate, resulting in target ubiquitylation and subsequent degradation. Higher extracellular K⁺ concentrations limit NCC phosphorylation, but this effect is attenuated in the absence of active cullins, suggesting that the responses on NCC are partly dependent on cullin activity. A lower extracellular K⁺ concentration increases SPAK and NCC phosphorylation, but not as much in the absence of active cullins. Although this suggests that the effects of low extracellular K⁺ on NCC phosphorylation are fully dependent of cullin activity, more likely is that in the absence of cullin activity WNK, SPAK, and NCC phosphorylation are already maximized and no further increases are possible. SR-substrate receptor; Adap.-adaptor protein.