NaPi-IIa and interacting partners

Abstract

Regulation of renal proximal tubular reabsorption of phosphate (Pi) is one of the critical steps in Pi homeostasis. Experimental evidence suggests that this regulation is achieved mainly by controlling the apical expression of the Na+-dependent Pi cotransporter type IIa (NaPi-IIa) in proximal tubules. Only recently have we started to obtain information regarding the molecular mechanisms that control the apical expression of NaPi-IIa. The first critical observation was the finding that truncation of only its last three amino acid residues has a strong effect on apical expression. A second major finding was the observation that the last intracellular loop of NaPi-IIa contains sequence information that confers parathyroid hormone (PTH) sensitivity. The use of the above domains of the cotransporter in yeast two-hybrid (Y2H) screening allowed the identification of proteins interacting with NaPi-IIa. Biochemical and morphological, as well as functional, analyses have allowed us to obtain insights into the physiological roles of such interactions, although our present knowledge is still far from complete.

Figure 1. Proteins that interact with the N-terminal, last intracellular loop and C-terminal cytoplasmic domains of NaPi-IIa

The expression of all interacting partners in renal proximal tubules was confirmed either by immunoblots, immunohistochemistry and/or RT-PCR. The abbreviations are: PTH-R, PTH receptors; PLC, phospholipase C; PDZ, PDZ domains; MERM, merlin-ezrin-radixin-moesin family; MERM-BD, MERM-binding domain; PKA, protein kinase A; D-AKAP2, dual A-kinase anchoring protein 2. The PDZ domains of NHERF1 and PDZK1 are indicated by rectangles. Interactions between proteins are illustrated either by showing direct contacts of a cartoon-form of each protein or by arrows.