# Functional Polarity of PTH Receptor Signaling: Cellular and Molecular Mechanisms

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $587,629

## Abstract

Project Summary
The goal of this project is to determine the mechanisms underlying the molecular and cellular endocrinology
of parathyroid hormone receptor (PTHR) signaling as it relates to phosphate and vitamin D balance. PTHR
is uniquely expressed on both apical and basolateral membranes of the polarized cells that form renal
proximal tubules. The biological consequences of bilateral PTHR expression or its origin are unknown. The
premise of the proposal is that characterizing asymmetric PTHR actions will fill a major gap in our
understanding of PTHR signaling and function and reconcile conflicting views of PTH action. Pilot studies
show that PTHR signals from both basolateral and apical membranes but only basolateral PTHR activation
induces transcription of the 1α-vitamin D hydroxylase (CYP27B1). Apical PTHR signaling primarily inhibits
phosphate transport. The molecular and cellular mechanisms regulating PTHR actions are incompletely
defined. The PTHR interacts at apical membranes with the PDZ scaffolding protein NHERF1, which tethers
the receptor and regulates G-protein signaling and function. Absence of NHERF1 or its downregulation
causes relocation of PTHR to basolateral membranes with an increased 1,25[OH]2D in mice and humans.
Preliminary data show that Scribble, a basolateral PDZ protein, exerts a reciprocal effect, where
downregulation causes accumulation of PTHR at apical membranes. We hypothesize that the polarized
PTHR arrangement arises from the segregated location of NHERF1 and Scribble. We advance a research
program to uncover new aspects of PTHR signaling in polarized kidney cells and test the central hypothesis
that polarized PTHR expression is driven by the asymmetric location of the PDZ adaptor proteins, Scribble
and NHERF, which in turn underlies the signaling bias of apical and basolateral PTHR actions on vitamin D
and phosphate homeostasis. We propose three closely linked aims to evaluate this idea. The first two aims
of address the hypothesis that basolateral PTHR activation preferentially stimulates the 1α-vitamin D
hydroxylase, whereas apical PTHR signaling primarily blocks Pi transport. Aim 1 will determine the role of
Scribble and NHERF in the generation of PTHR polarity and its asymmetric signaling in human kidney
proximal tubule epithelial cells. Aim 2 uses live-cell FRET microscopy and other state-of-the art
fluorescence techniques to characterize basolateral and apical membrane signaling properties of PTHR and
the effect of NHERF1 and Scribble on biased G protein signaling. Aim 3 will delineate the in vivo actions of
polarized proximal tubule PTHR by testing the role of Scribble on PTHR-dependent vitamin D and
phosphate metabolism using a novel, conditional proximal tubule Scribble knockout mouse model that we
generated. The outcomes will frame innovative therapeutic approaches targeting disorders of mineral
metabolism.

## Key facts

- **NIH application ID:** 9978053
- **Project number:** 5R01DK111427-04
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Peter A Friedman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $587,629
- **Award type:** 5
- **Project period:** 2017-08-20 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9978053

## Citation

> US National Institutes of Health, RePORTER application 9978053, Functional Polarity of PTH Receptor Signaling: Cellular and Molecular Mechanisms (5R01DK111427-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9978053. Licensed CC0.

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