Wenhan Chang 1 , Chia-Ling Tu 1 , Frederic Jean-Alphonse 2 , Amanda Herberger 1 , Zhiqiang Cheng 1 , Jenna Hwong 1 , Hanson Ho 1 , Alfred Li 1 , Dawei Wang 2 , Hongda Liu 2 , Alex D. White 2 , 3 , Insoo Suh 4 , Wen Shen 4 , Quan-Yang Duh 4 , Elham Khanafshar 5 , Dolores M. Shoback 1 , Kunhong Xiao 2 , Jean-Pierre Vilardaga 2
09 March 2020
Molecular mechanisms mediating tonic secretion of parathyroid hormone (PTH) in response to hypocalcemia and hyperparathyroidism (HPT) are unclear. Here we demonstrate increased heterocomplex formation between the calcium-sensing receptor (CaSR) and metabotropic GABA B1 receptor (GABA B1R) in hyperplastic parathyroid glands (PTGs) of patients with primary and secondary HPT. Targeted ablation of GABA B1R or glutamic acid decarboxylase 1 and 2 in PTGs produces hypocalcemia and hypoparathyroidism and prevents PTH hypersecretion in PTGs cultured from mouse models of hereditary HPT and dietary calcium-deficiency. Co-binding of CaSR/GABA B1R 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 B1R in mediating tonic PTH secretion of PTGs and ascribe aberrant activities of CaSR/GABA B1R heteromer to HPT.