Open AccessPTH hypersecretion triggered by a GABAB1 and Ca2+-sensing receptor heterocomplex in hyperparathyroidism
Author(s) -
Wenhan Chang,
Chengjian Tu,
Frédéric JeanAlphonse,
Amanda L. Herberger,
Zhiqiang Cheng,
Jenna Hwong,
Hanson Ho,
Alfred Li,
Dawei Wang,
Hongda Liu,
Anna Marie White,
Insoo Suh,
Wen T. Shen,
QuanYang Duh,
Elham Khanafshar,
Dolores Shoback,
Kunhong Xiao,
JeanPierre Vilardaga
Publication year - 2020
Publication title -
nature metabolism
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.834
H-Index - 22
ISSN - 2522-5812
DOI - 10.1038/s42255-020-0175-z
Subject(s) - calcium sensing receptor , medicine , endocrinology , calcimimetic , parathyroid hormone , hypocalcaemia , chemistry , secondary hyperparathyroidism , receptor , calcium , autocrine signalling , biology
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.