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PTH-Induced Downregulation of the Type IIa Na/P_i-Cotransporter Is Independent of Known Endocytic Motifs

Institute of Physiology, University of Zürich, Switzerland.

Correspondence to Dr. Heini Murer, Physiologisches Institut der Universität Zürich, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland. Phone: 41-1-635-50-30; Fax: 41-1-635-57-15; E-mail: hmurer{at}access.unizh.ch

Abstract. Parathyroid hormone (PTH)-induced inhibition of renal proximal tubular Na/P_i cotransport involves two consecutive steps: endocytosis followed by lysosomal degradation of the type IIa Na/P_i cotransporter. Tyrosine-, dileucine-, and diacidic-based motifs are suggested to be involved in endocytosis and/or lysosomal targeting of different plasma membrane proteins. The rat type IIa cotransporter (NaPi2) contains two cytoplasmic tyrosine residues (Y) within sequences highly homologous to tyrosine-based motifs (GY₄₀₂FAM and Y₅₀₉RWF), three cytoplasmic dileucine (LL₁₀₁, LL₃₇₄, and LI₅₉₁) and two cytoplasmic diacidic motifs (EE₈₁ and EE₆₁₆). We studied the role of these motifs on the PTH-induced retrieval and lysosomal degradation of the NaPi2 cotransporter. To follow its trafficking in vivo, the NaPi2 protein was fused to the carboxyl-terminal end of the enhanced green fluorescence protein. This fusion did not impair the apical targeting or the PTH-induced endocytosis of the wild-type cotransporter when transfected in opossum kidney cells. Single and multiple Y and LL mutants retained the apical targeting and the PTH-induced degradation. Mutations of the diacidic motifs were also without effect. These data suggest that the above three motifs are not required for the PTH-induced internalization and/or degradation of the cotransporter.

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