# Regulation of Parathyroid Functions By G-Protein Coupled Receptors

> **NIH NIH R01** · NORTHERN CALIFORNIA INSTITUTE/RES/EDU · 2023 · $432,314

## Abstract

Parathyroid glands (PTGs) control mineral, hormonal, and skeletal homeostasis by adjusting parathyroid
hormone (PTH) secretion in response to changes in serum [Ca2+]. It is well documented that activation of
homomeric extracellular calcium-sensing receptor (CaSR) by raising serum [Ca2+] suppresses PTH secretion.
However, the mechanisms promoting PTH secretion at hypocalcemic and various hyperparathyroidism (HPT)
states due to CaSR-deficiency have not been explored. Our pilot data raise a novel hypothesis of a novel
autocrine mechanism by which GABA and GABAB1R regulate G protein signaling of the CaSR to promote PTH
secretion. Multi-disciplinary approaches to be performed by two highly complementary teams at University of
Pittsburgh and University of California San Francisco will be employed to test this hypothesis through 3 specific
aims. Aim 1 will first demonstrate the physiopathological relevance of the functional interaction between the
CaSR and GABAB1R in PTGs by studying parathyroid cell (PTC)-specific GABAB1R and/or CaSR knockout mice
in the contexts of hypocalcemia and different forms of HPT challenges (i.e., CaSR-deficiency or chronical kidney
disease) in vivo and human PTGs excised from patients with primary and secondary HPT. Aim 2 will define the
biological actions of Gad1/2 in regulating PTG functions by studying the effects of PTC-specific Gad1 and Gad2
double knockout in conditions of Ca2+ deficiency and various HPT states in mice and assessing Gad1/2 and
GABA expression in human PTGs excised from patients with primary and secondary HPT. Aim 3 will delineate
molecular mechanisms by which the CaSR/GABAB1R heteromers alter efficacy of G-protein activation of the
CaSR and its consequence for PTH secretion and GABA production in cultured parathyroid-derived PTH-C1
cells. Optical (FRET, TIRF, BiFC) and biochemical techniques will be used to test the theory that PTH release
and GABA synthesis are controlled through mechanisms involving the allosteric action of GABAB1R on CaSR
signaling via receptor heteromerization that inhibits Ca2+-mediated Gq/11 and Gi signal transduction and promote
PTH secretion. Successful completion of this project will help to develop new regimens to manage PTH hypo-
or hyper-secretion and related endocrine and skeletal diseases and prevent unwanted side-effects of GABAB1R
agonists and antagonists prescribed to patients with neurological disorders.

## Key facts

- **NIH application ID:** 10693870
- **Project number:** 5R01DK122259-05
- **Recipient organization:** NORTHERN CALIFORNIA INSTITUTE/RES/EDU
- **Principal Investigator:** Wenhan Chang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $432,314
- **Award type:** 5
- **Project period:** 2019-09-12 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10693870

## Citation

> US National Institutes of Health, RePORTER application 10693870, Regulation of Parathyroid Functions By G-Protein Coupled Receptors (5R01DK122259-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10693870. Licensed CC0.

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