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

  • Author(s): Chang, Wenhan
  • Tu, Chia-Ling
  • Jean-Alphonse, Frederic G
  • Herberger, Amanda
  • Cheng, Zhiqiang
  • Hwong, Jenna
  • Ho, Hanson
  • Li, Alfred
  • Wang, Dawei
  • Liu, Hongda
  • White, Alex D
  • Suh, Insoo
  • Shen, Wen
  • Duh, Quan-Yang
  • Khanafshar, Elham
  • Shoback, Dolores M
  • Xiao, Kunhong
  • Vilardaga, Jean-Pierre
  • et al.
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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