# Heterodimerization of the Calcium-sensing receptor with the GabaB receptors in the breast.

> **NIH NIH R01** · YALE UNIVERSITY · 2020 · $460,399

## Abstract

PROJECT SUMMARY/ABSTRACT
 The calcium-sensing receptor (CaSR) is a G protein-coupled receptor (GPCR) that signals in response
to changes in extracellular calcium. It functions as an obligate dimer and couples to different G-proteins,
including Gai or Gas, in a context- or cell type-specific manner. The CaSR is widely expressed and alters
proliferation, differentiation, death and ion transport in a variety of cell types, including mammary epithelial cells
(MECs), where it regulates the production of parathyroid hormone-related protein (PTHrP) and milk calcium
transport. During lactation, activation of the CaSR on MECs inhibits PTHrP secretion by stimulating Gai and
reducing cAMP levels. However, in breast cancer cells, activation of the CaSR increases, rather than
decreases, PTHrP secretion because, in these cells, the CaSR activates Gas and increases cAMP levels. The
CaSR has important functions in both lactation physiology and breast cancer pathophysiology, so it is critical to
better understand the regulation of its downstream signaling events in breast epithelial cells. Emerging data
demonstrate that the CaSR can heterodimerize with the 2 metabotropic, GabaB receptors, GABBR1 and
GABBR2 and the central premise of this application is that heterodimerization of the CaSR with
GABBR1 and/or GABBR2 alters CaSR signaling, PTHrP production and transepithelial calcium
transport by mammary epithelial cells. Specifically, we hypothesize that, during lactation, reductions in
GABBR1 expression and increases in GABBR2 expression promote the formation of CaSR/GABBR2
heterodimers in MECs, which, in turn, increases membrane CaSR expression and reinforces coupling of the
CaSR to Gai. In order to explore this hypothesis, we propose 3 Specific Aims. Aim 1 will examine how
heterodimerization with GABBR1 or GABBR2 alters CaSR expression, signaling and PTHrP production in
breast epithelial cells in vitro. Aim 2 will use genetically modified mice to examine whether heterodimerization
with GABBR2 regulates CaSR expression and function in the lactating breast in vivo. Aim 3 will use
genetically modified mice to examine whether heterodimerization with GABBR1 regulates CaSR expression
and function in the lactating breast in vivo. The studies outlined in this proposal will explore novel biology of
great importance for lactation physiology that also has implications for breast cancer pathophysiology. These
studies have the potential to discover novel ways to target the CaSR therapeutically.

## Key facts

- **NIH application ID:** 10050698
- **Project number:** 1R01HD100468-01A1
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** John J Wysolmerski
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $460,399
- **Award type:** 1
- **Project period:** 2020-09-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10050698

## Citation

> US National Institutes of Health, RePORTER application 10050698, Heterodimerization of the Calcium-sensing receptor with the GabaB receptors in the breast. (1R01HD100468-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10050698. Licensed CC0.

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