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1 Physiology, Zurich University, Zurich, Zurich, Switzerland
2 Anatomy, Zurich University, Zurich, Zurich, Switzerland
3 Genzyme Corporation, Framingham, MA, USA
* To whom correspondence should be addressed. E-mail: hernando{at}phsiol.unizh.ch.
The type IIa Na/Pi-cotransporter (NaPi-IIa) and the Na/H-exchanger regulatory factor 1 (NHERF1) colocalize in the apical membrane of proximal tubular cells. Both proteins interact in vitro. Here, the interaction between NaPi-IIa and NHERF1 is further documented by coimmunoprecipitation and copulldown assays. NaPi-IIa is endocytosed and degraded in lysosomes upon parathyroid hormone (PTH) treatment. To investigate the effect of PTH on the NaPi-IIa/NHERF1 association, we first compared the localization of both proteins after PTH treatment. In mouse proximal tubules and OK cells NaPi-IIa was removed from the apical membrane after hormonal treatment; however, NHERF1 remained at the membrane. Moreover, PTH led to degradation of NaPi-IIa, without changes in the amount of NHERF1. The effect of PTH on the NaPi-IIa/NHERF1 interaction was further studied by coimmunoprecipitation. PTH treatment reduced the amount of NaPi-IIa coimmunoprecipitated with NHERF antibodies. PTH-induced internalization of NaPi-IIa requires PKA and PKC; therefore we next analyzed whether PTH induces changes in the phosphorylation state of either partner. NHERF1 was constitutively phosphorylated. Moreover, in mouse kidney slices PTH induced an increase of NHERF1 phosphorylation; independent activation of PKA or PKC also resulted in an increased phosphorylation of NHERF1 in kidney slices. However, NaPi-IIa was not phosphorylated either basally or after exposure to PTH. In summary, our study supports an interaction between NHERF1 and NaPi-IIa based on their brush border membrane colocalization and in vitro coimmunoprecipitation/copulldowns. Furthermore, PTH weakens this interaction, as evidenced by different in situ/in vivo behavior. The PTH effect takes place in the presence of increased phosphorylation of NHERF1.
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