Sorting Protein-Related Receptor Sorla Is Involved In Regulation Of Renal Na+-K+-2cl-Cotransporter Through Interaction With An Isoform Of Calcineurin Phosphatase

Activity of the Na+‐K+‐2Cl‐cotransporter (NKCC2) of the thick ascending limb (TAL) is dependent on its N‐terminal phosphorylation. Sorting protein‐related receptor SorLA was shown to facilitate this process. To clarify the interference between SorLA and NKCC2 we have evaluated the profile of relevant kinases and phosphatases in TAL of SorLA‐deficient (Sorla−/−) compared to wild‐type (WT) mice. SorLA‐deficiency was associated with nearly absent NKCC2 phosphorylation (−97%). Levels of the SPAK‐OSR1 kinases were not changed while the abundance of the calcineurin phosphatase PP2BAβ was significantly increased in SorLA‐deficiencient animals (+201%). Confocal analysis revealed apical accumulation of the phosphatase in TAL of Sorla−/− mice. The interaction of NKCC2 with PP2BAβ was verified by co‐immunoprecipitation. Application of a calcineurin inhibitor cyclosporine in cultured TAL cells induced an increase of NKCC2 phosphorylation. Our results establish PP2BAβ as a relevant phosphatase responsible for the dephosphorylation of NKCC2 and provide evidence that SorLA may mediate degradation of PP2BAβ thus facilitating the phosphorylation of the transporter.