PTH hypersecretion triggered by a GABAB1 and Ca2+-sensing receptor heterocomplex in hyperparathyroidism.

Nature Metabolism
Wenhan ChangJean-Pierre Vilardaga

Abstract

Molecular mechanisms mediating tonic secretion of parathyroid hormone (PTH) in response to hypocalcaemia and hyperparathyroidism (HPT) are unclear. Here we demonstrate increased heterocomplex formation between the calcium-sensing receptor (CaSR) and metabotropic γ-aminobutyric acid (GABA) B1 receptor (GABAB1R) in hyperplastic parathyroid glands (PTGs) of patients with primary and secondary HPT. Targeted ablation of GABAB1R or glutamic acid decarboxylase 1 and 2 in PTGs produces hypocalcaemia and hypoparathyroidism, and prevents PTH hypersecretion in PTGs cultured from mouse models of hereditary HPT and dietary calcium-deficiency. Cobinding of the CaSR/GABAB1R complex by baclofen and high extracellular calcium blocks the coupling of heterotrimeric G-proteins to homomeric CaSRs in cultured cells and promotes PTH secretion in cultured mouse PTGs. These results combined with the ability of PTG to synthesize GABA support a critical autocrine action of GABA/GABAB1R in mediating tonic PTH secretion of PTGs and ascribe aberrant activities of CaSR/GABAB1R heteromer to HPT.

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Citations

Jun 24, 2020·The Journal of Biological Chemistry·Ieva Sutkeviciute, Jean-Pierre Vilardaga
Mar 24, 2020·Nature Reviews. Endocrinology·Shimona Starling
Mar 13, 2021·Current Opinion in Physiology·Xiaonan DengJenny J Yang
May 30, 2021·Science Advances·Hamidreza ShayeVadim Cherezov
Jun 19, 2021·Current Opinion in Endocrine and Metabolic Research·Caroline M Gorvin
Jul 18, 2021·The Journal of Clinical Endocrinology and Metabolism·James KohJulie A Sosa

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Methods Mentioned

BETA
PCR
proximity ligation assay
coimmunoprecipitation
immunoprecipitation
pull down
FRET
transfections
transfection
fluorescence
ELISA

Software Mentioned

GraphPad Prism
GraphPad
OriginPro
TissueQuest Analysis
Prism
MassLynx
Multicolour BiFC

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