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      PTH Hypersecretion Triggered by a GABA B1 and Ca 2+-sensing Receptor Heterocomplex in Hyperparathyroidism

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          Abstract

          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.

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          Bimolecular fluorescence complementation (BiFC) analysis as a probe of protein interactions in living cells.

          Tom Kerppola (2008)
          Protein interactions are a fundamental mechanism for the generation of biological regulatory specificity. The study of protein interactions in living cells is of particular significance because the interactions that occur in a particular cell depend on the full complement of proteins present in the cell and the external stimuli that influence the cell. Bimolecular fluorescence complementation (BiFC) analysis enables direct visualization of protein interactions in living cells. The BiFC assay is based on the association between two nonfluorescent fragments of a fluorescent protein when they are brought in proximity to each other by an interaction between proteins fused to the fragments. Numerous protein interactions have been visualized using the BiFC assay in many different cell types and organisms. The BiFC assay is technically straightforward and can be performed using standard molecular biology and cell culture reagents and a regular fluorescence microscope or flow cytometer.
          Article 0 comments Cited 192 times – based on 0 reviews     Review now
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            Design and implementation of bimolecular fluorescence complementation (BiFC) assays for the visualization of protein interactions in living cells.

            Tom Kerppola (2006)
            Bimolecular fluorescence complementation (BiFC) analysis enables direct visualization of protein interactions in living cells. The BiFC assay is based on the discoveries that two non-fluorescent fragments of a fluorescent protein can form a fluorescent complex and that the association of the fragments can be facilitated when they are fused to two proteins that interact with each other. BiFC must be confirmed by parallel analysis of proteins in which the interaction interface has been mutated. It is not necessary for the interaction partners to juxtapose the fragments within a specific distance of each other because they can associate when they are tethered to a complex with flexible linkers. It is also not necessary for the interaction partners to form a complex with a long half-life or a high occupancy since the fragments can associate in a transient complex and un-associated fusion proteins do not interfere with detection of the complex. Many interactions can be visualized when the fusion proteins are expressed at levels comparable to their endogenous counterparts. The BiFC assay has been used for the visualization of interactions between many types of proteins in different subcellular locations and in different cell types and organisms. It is technically straightforward and can be performed using a regular fluorescence microscope and standard molecular biology and cell culture reagents.
            Article 0 comments Cited 159 times – based on 0 reviews     Review now
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              The calcium-sensing receptor in physiology and in calcitropic and noncalcitropic diseases

              Fadil M. Hannan, Enikö Kállay, Wenhan Chang … (2018)
              The Ca 2+ -sensing receptor (CaSR) is a dimeric family C G-protein-coupled receptor that is expressed in calcitropic tissues such as the parathyroid glands and kidneys, and signals via G-proteins and beta-arrestin. The CaSR plays a pivotal role in bone and mineral metabolism by regulating parathyroid hormone secretion, urinary Ca 2+ excretion, skeletal development and lactation. The importance of the CaSR for these calcitropic processes is highlighted by loss- and gain-of-function CaSR mutations, which cause familial hypocalciuric hypercalcaemia and autosomal dominant hypocalcaemia, respectively, and also by alterations in parathyroid CaSR expression, which contribute to the pathogenesis of primary and secondary hyperparathyroidism. Moreover, the CaSR is an established therapeutic target for hyperparathyroid disorders. The CaSR is also expressed in organs not involved in Ca 2+ homeostasis, where it has non-calcitropic roles that include lung and neuronal development, vascular tone, gastro-intestinal nutrient sensing, secretion of insulin and entero-endocrine hormones, and wound healing. Furthermore, abnormal expression or function of the CaSR is implicated in cardiovascular and neurological diseases, as well as in asthma, and the CaSR is reported to protect against colorectal cancer and neuroblastoma, but increase the malignant potential of prostate and breast cancers. This review will discuss these physiological and pathophysiological roles of the CaSR.
              Article 0 comments Cited 109 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-journal-id): 101736592
                Journal ID (pubmed-jr-id): 48119
                Journal ID (nlm-ta): Nat Metab
                Journal ID (iso-abbrev): Nat Metab
                Title: Nature metabolism
                ISSN (Electronic): 2522-5812
                Publication date Nihms-submitted: 14 February 2020
                Publication date (Electronic): 09 March 2020
                Publication date (Print): March 2020
                Publication date PMC-release: 09 September 2020
                Volume: 2
                Issue: 3
                Pages: 243-255
                Affiliations
                [1 ]Endocrine Research Unit, Department of Veterans Affairs Medical Center, and University of California, San Francisco, CA, USA.
                [2 ]Laboratory for GPCR Biology, Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
                [3 ]Graduate Program in Molecular Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
                [4 ]Department of Surgery, University of California, San Francisco, CA, USA.
                [5 ]Department of Pathology, University of California, San Francisco, CA, USA.
                Author notes

                AUTHOR CONTRIBUTIONS

                W.C., A.H., D.M.S., C.-L.T., and J.-P.V. designed the study. W.C., A.H., C.-L.T., J.H., H.H., A.L., Z.C. and J.-P.V. conducted the study. W.C., A.H., A.D.W., F.J.-A., C.-L.T., J.H., H.H., A.L., Z.C. and J.-P.V. collected data. Q.-Y.D., W.S., and I.S. evaluated the patients, obtained informed consent, and conducted the surgeries for all human PTG studies. E.K., D.M.S., and A.H. reviewed clinical and pathology records related to human PTG samples. K.X. provided expertise with mass spectroscopy and performed MS experiments with support of H.L. and D.W. W.C., A.H., C.-L.T., and J.-P.V. performed data analyses. W.C., A.H., E.K., D.M.S., C.-L.T., and J.-P.V. interpreted the data. W.C. and J.-P.V. wrote the manuscript with support of A.H., C.-L.T., D.M.S. and H.K. W.C. and J.-P.V. take responsibility for the integrity of the data analysis.

                [* ] Corresponding Authors: W.C. ( wenhan.chang@ 123456ucsf.edu ) or J.-P.V. ( jpv@ 123456pitt.edu )
                Author information
                http://orcid.org/0000-0001-6583-7176
                http://orcid.org/0000-0002-1217-1435
                Article
                Manuscript ID: NIHMS1550595
                DOI: 10.1038/s42255-020-0175-z
                PMC ID: 7377265
                PubMed ID: 32694772
                SO-VID: bc9c2899-1769-43de-8e67-8700805fb9ae
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                Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms

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                Subject: Article

                Keywords: parathyroid glands,ca2+-sensing receptor,gabab1 receptor,hyperparathyroidism,pth secretion,family c gpcr
                Data availability:
                Keywords: parathyroid glands, ca2+-sensing receptor, gabab1 receptor, hyperparathyroidism, pth secretion, family c gpcr

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