Heterogeneity of G protein activation by the calcium-sensing receptor
| العنوان: | Heterogeneity of G protein activation by the calcium-sensing receptor |
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| المؤلفون: | Caroline M Gorvin, Hasnat Ali Abid, Asuka Inoue |
| المصدر: | Journal of Molecular Endocrinology |
| بيانات النشر: | Bioscientifica, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | 0301 basic medicine, calcium signalling, Gs alpha subunit, G protein, 030209 endocrinology & metabolism, Inositol 1,4,5-Trisphosphate, Kidney, Parathyroid Glands, Gene Knockout Techniques, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, GTP-Binding Proteins, Cyclic AMP, Humans, Protein Isoforms, G protein-coupled receptor, Receptor, Pancreas, Molecular Biology, Calcium signaling, calcium homeostasis, biology, Chemistry, Gene Expression Profiling, Research, parathyroid and bone, Cell biology, HEK293 Cells, 030104 developmental biology, Gq alpha subunit, Organ Specificity, Multigene Family, biology.protein, Signal transduction, Calcium-sensing receptor, Receptors, Calcium-Sensing, Biomarkers, signal transduction, Protein Binding |
| الوصف: | The calcium-sensing receptor (CaSR) is a G protein-coupled receptor that plays a fundamental role in extracellular calcium (Ca2+e) homeostasis by regulating parathyroid hormone release and urinary calcium excretion. The CaSR has been described to activate all four G protein subfamilies (Gαq/11, Gαi/o, Gα12/13, Gαs), and mutations in the receptor that cause hyper/hypocalcaemia, have been described to bias receptor signalling. However, many of these studies are based on measurements of second messengers or gene transcription that occurs many steps downstream of receptor activation and can represent convergence points of several signalling pathways. Therefore, to assess CaSR-mediated G protein activation directly, we took advantage of a recently described NanoBiT G protein dissociation assay system. Our studies, performed in HEK293 cells stably expressing CaSR, demonstrate that Ca2+e stimulation activates all Gαq/11 family and several Gαi/o family proteins, although Gαz was not activated. CaSR stimulated dissociation of Gα12/13 and Gαs from Gβ-subunits, but this occurred at a slower rate than that of other Gα-subunits. Investigation of cDNA expression of G proteins in three tissues abundantly expressing CaSR, the parathyroids, kidneys and pancreas, showed Gα11, Gαz, Gαi1 and Gα13 genes were highly expressed in parathyroid tissue, indicating CaSR most likely activates Gα11 and Gαi1 in parathyroids. In kidney and pancreas, the majority of G proteins were similarly expressed, suggesting CaSR may activate multiple G proteins in these cells. Thus, these studies validate a single assay system that can be used to robustly assess CaSR variants and biased signalling and could be utilised in the development of new pharmacological compounds targeting CaSR. |
| تدمد: | 1479-6813 0952-5041 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::4e15b4b32a8603327fe8356c28185897 https://doi.org/10.1530/jme-21-0058 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....4e15b4b32a8603327fe8356c28185897 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14796813 09525041 |
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