Defective coupling of apical PTH receptors to phospholipase C prevents internalization of the Na+-phosphate cotransporter NaPi-IIa in Nherf1-deficient mice |
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Authors: | Capuano Paola Bacic Desa Roos Marcel Gisler Serge M Stange Gerti Biber Jürg Kaissling Brigitte Weinman Edward J Shenolikar Shirish Wagner Carsten A Murer Heini |
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Institution: | Institute of Physiology, Univ. of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland. |
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Abstract: | Phosphate reabsorption in the renal proximal tubule occurs mostly via the type IIa Na+-phosphate cotransporter (NaPi-IIa) in the brush border membrane (BBM). The activity and localization of NaPi-IIa are regulated, among other factors, by parathyroid hormone (PTH). NaPi-IIa interacts in vitro via its last three COOH-terminal amino acids with the PDZ protein Na+/H+-exchanger isoform 3 regulatory factor (NHERF)-1 (NHERF1). Renal phosphate reabsorption in Nherf1-deficient mice is altered, and NaPi-IIa expression in the BBM is reduced. In addition, it has been proposed that NHERF1 and NHERF2 are important for the coupling of PTH receptors (PTHRs) to phospholipase C (PLC) and the activation of the protein kinase C pathway. We tested the role of NHERF1 in the regulation of NaPi-IIa by PTH in Nherf1-deficient mice. Immunohistochemistry and Western blotting demonstrated that stimulation of apical and basolateral receptors with PTH-(134) led to internalization of NaPi-IIa in wild-type and Nherf1-deficient mice. Stimulation of only apical receptors with PTH-(334) failed to induce internalization in Nherf1-deficient mice. Expression and localization of apical PTHRs were similar in wild-type and Nherf1-deficient mice. Activation of the protein kinase C- and A-dependent pathways with 1,2-dioctanoyl-sn-glycerol or 8-bromo-cAMP induced normal internalization of NaPi-IIa in wild-type, as well as Nherf1-deficient, mice. Stimulation of PLC activity due to apical PTHRs was impaired in Nherf1-deficient mice. These data suggest that NHERF1 in the proximal tubule is important for PTH-induced internalization of NaPi-IIa and, specifically, couples the apical PTHR to PLC. phosphate cotransporter; PDZ protein; parathyroid hormone; proximal tubule |
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