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甲状旁腺功能亢进症中由γ-氨基丁酸和钙敏感受体异源复合物触发的甲状旁腺激素分泌过多。

PTH hypersecretion triggered by a GABA and Ca-sensing receptor heterocomplex in hyperparathyroidism.

作者信息

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

机构信息

Endocrine Research Unit, Department of Veterans Affairs Medical Center, University of California, San Francisco, CA, USA.

Laboratory for GPCR Biology, Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.

出版信息

Nat Metab. 2020 Mar;2(3):243-255. doi: 10.1038/s42255-020-0175-z. Epub 2020 Mar 9.

DOI:10.1038/s42255-020-0175-z
PMID:32694772
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7377265/
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) B receptor (GABAR) in hyperplastic parathyroid glands (PTGs) of patients with primary and secondary HPT. Targeted ablation of GABAR 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/GABAR 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/GABAR in mediating tonic PTH secretion of PTGs and ascribe aberrant activities of CaSR/GABAR heteromer to HPT.

摘要

介导甲状旁腺激素（PTH）对低钙血症和甲状旁腺功能亢进（HPT）产生强直性分泌的分子机制尚不清楚。在此，我们证明在原发性和继发性HPT患者的增生性甲状旁腺（PTG）中，钙敏感受体（CaSR）与代谢型γ-氨基丁酸（GABA）B受体（GABAR）之间的异源复合物形成增加。在PTG中靶向消融GABAR或谷氨酸脱羧酶1和2会导致低钙血症和甲状旁腺功能减退，并防止从遗传性HPT和饮食性钙缺乏小鼠模型培养的PTG中PTH分泌过多。巴氯芬和高细胞外钙对CaSR/GABAR复合物的共结合可阻断培养细胞中异三聚体G蛋白与同聚体CaSR的偶联，并促进培养的小鼠PTG中PTH的分泌。这些结果与PTG合成GABA的能力相结合，支持了GABA/GABAR在介导PTG强直性PTH分泌中的关键自分泌作用，并将CaSR/GABAR异聚体的异常活性归因于HPT。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4c3a/7377265/f4f1d72d76f5/nihms-1550595-f0007.jpg
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