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 (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 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_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.

尚不清楚介导低钙血症和甲状旁腺功能亢进症（HPT）应答的甲状旁腺激素（PTH）补品分泌的分子机制。在这里，我们证明原发性和继发性HPT患者的增生性甲状旁腺（PTG）中钙敏感受体（CaSR）和代谢型γ-氨基丁酸（GABA）B ₁受体（GABA _B1 R）之间的杂合物形成增加。在PTG中靶向消融GABA _B1 R或谷氨酸脱羧酶1和2会产生低钙血症和甲状旁腺功能低下，并防止从遗传性HPT和饮食钙缺乏症小鼠模型培养的PTG中PTH过度分泌。CaSR / GABA _B1的结合巴氯芬和高细胞外钙的R复合物可阻止异三聚体G蛋白与培养细胞中同质CaSR的偶联，并促进培养小鼠PTG中PTH的分泌。这些结果与PTG合成GABA的能力相结合，支持GABA / GABA _B1 R在介导PTG的补品PTH分泌和CaSR / GABA _B1 R异源异构体对HPT异常活性方面的关键自分泌作用。