Endocrine Abstracts

Parathyroid hormone (PTH) exerts important metabolic effects on the kidney and is responsible for regulating phosphate transport by proximal tubules and calcium absorption by distal tubules. These effects are mediated by the type 1 PTH receptor (PTH1R), which is prominently expressed in both nephron segments. However, the signaling pathways employed by proximal and distal PTH1Rs differ markedly. Recent work reveals the apparent basis by which PTH receptors signal through cAMP in some instances but through Ca/inositol phosphate in others. This signaling switch is the Na/H exchange regulatory factor NHERF1 (EBP50). NHERF1, and its related protein NHERF2 (E3KARP), are cytoplasmic adapter proteins containing two PDZ domains and an ERM domain. NHERF1 serves as a protein scaffold bringing together membrane and non-membrane proteins. NHERF1 is expressed in proximal but not in distal tubule cells. We found that PTH1R activation and internalization could be dissociated and that this dissociation was controlled by NHERF1. PTH(1-34) and PTH(1-84) activated and internalized the PTH1R in both proximal and distal tubule cells. PTH(7-34) and PTH(7-84) did not activate the PTH1R but caused extensive internalization that was limited to distal tubule cells. The ability of non-activating PTH peptides to internalize the PTH1R was due to the absence of NHERF1. Introducing NHERF1 in distal cells blocked the effects of PTH(7-34). Conversely, inhibiting NHERF1 in proximal cells permitted PTH(7-34) to internalize the PTH1R. Mutation of the PTH1R PDZ-binding motif abrogated interaction of the receptor with NHERF1. These mutated receptors were fully functional but were now internalized in response to PTH(7-34) even in NHERF1-expressing cells. These findings show that NHERF1 acts as a molecular switch that regulates the conditional efficacy of PTH fragments. The findings may be important in understanding the PTH resistance of renal failure, where PTH(7-84) accumulates and may internalize and downregulate PTH1 receptors.