PTH hypersecretion triggered by a GABAB1 and Ca2+-sensing receptor heterocomplex in hyperparathyroidism
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) B 1 recept...
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Veröffentlicht in: | Nature metabolism 2020-03, Vol.2 (3), p.243-255 |
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Hauptverfasser: | , , , , , , , , , , , , , , , , , |
Format: | Artikel |
Sprache: | eng |
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Zusammenfassung: | 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) B
1
receptor (GABA
B1
R) in hyperplastic parathyroid glands (PTGs) of patients with primary and secondary HPT. Targeted ablation of GABA
B1
R 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/GABA
B1
R 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/GABA
B1
R in mediating tonic PTH secretion of PTGs and ascribe aberrant activities of CaSR/GABA
B1
R heteromer to HPT.
Parathyroid glands regulate calcium homeostasis by secreting parathyroid hormone. Chang et al. demonstrate that in parathyroid glands GABA receptor GABAB1R makes a heterocomplex with the calcium-sensing receptor and regulates the secretion of parathyroid hormone. |
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ISSN: | 2522-5812 2522-5812 |
DOI: | 10.1038/s42255-020-0175-z |