ESPEYB19 5. Bone, Growth Plate and Mineral Metabolism Advances in skeletal biology (4 abstracts)
5.15. Asymmetric activation of the calcium-sensing receptor homodimer
Gao Y , Robertson MJ , Rahman SN , Seven AB , Zhang C , Meyerowitz JG , Panova O , Hannan FM , Thakker RV , Bräuner-Osborne H , Mathiesen JM & Skiniotis G
Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA
Nature. 2021 Jul;595(7867):455-459.Abstract: https://pubmed-ncbi-nlm-nih-gov/34194040/
In brief: Using cryo-electron microscopy, the calcium-sensing receptor (CaSR) is visualized with different ligands demonstrating, in great detail, how calcimimetic drugs lock the CaSR homodimer in an assymetric configuration, exposing one of the two protomers for G-protein coupling, whereas calciolytic drugs promote the symmetric configuration thereby preventing G-protein coupling.
Commentary: The calcium-sensing receptor (CaSR) is a seven-transmembrane receptor that can sense extracellular calcium levels at the cell surface. CaSR regulates calcium homeostasis primarily through its actions in the parathyroid gland and kidneys, where its activation by elevated circulating Ca2+ leads to decreases in parathyroid hormone (PTH) secretion and renal tubular Ca2+ resorption. Loss-of-function mutations of CaSR cause hypercalcemia as in neonatal severe hyperparathyrodism or familial hypocalciuric hypercalcaemia type 1 (FHH1). Conversely, gain-of-function CaSR mutations cause hypocalcaemia as in autosomal dominant hypocalcaemia type 1 (ADH1). Clinically, calcimimetic medications e.g. cinacalcet, are used for the treatment of FHH1, while calcilytic drugs currently are in clinical trials for the treatment of ADH1.
The authors expressed near-full-length human CaSR and produced cryo-electron microscopy images that show CaSR bound to Ca2+ and different calcilytic or calcimimetic drug molecules. The study visulizes how receptor activation results in asymmetry in the homodimer and therefore G-protein coupling and the specific positions where calcimimetic drugs bind and stabilize the asymmetric, active configuration as well as where and how calciolytic drugs bind and lock the receptor in its symmetric, inactive configuration. The study provides detailed images of the fundamental allosteric mechanisms that control CaSR signalling through G-protein. These findings will aid in the design of improved molecules for targeting of the CaSR and potenially also for other G-protein coupled receptors.
Volume 19
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ESPE Yearbook of Paediatric Endocrinology
ISSN 1662-4009 (Online)
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