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Endocrine Abstracts (2018) 59 APW1.1 | DOI: 10.1530/endoabs.59.APW1.1

1Institute of Metabolism and Systems Research (IMSR), University of Birmingham, Birmingham, UK; 2Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham, Birmingham, UK.


This year marks 25 years since the calcium-sensing receptor (CaSR) was first identified in bovine parathyroid and the receptor has since emerged as a fundamental contributor to extracellular calcium (Ca2+e) homeostasis, by regulating parathyroid hormone release and urinary calcium excretion. The CaSR is a class C GPCR that is functionally active as a homodimer. It couples to multiple G-protein subtypes to activate intracellular calcium mobilisation and mitogen-activated protein kinase signalling, induce membrane ruffling and suppress cAMP pathways. The importance of the CaSR in the regulation of Ca2+e has been highlighted by the identification of >230 germline loss- and gain-of-function CaSR mutations that give rise to disorders of calcium homeostasis, including familial hypocalciuric hypercalcaemia (FHH) and autosomal dominant hypocalcaemia (ADH). Functional studies of these disease-associated mutations have demonstrated that CaSR signals in a biased manner and have revealed specific residues important for receptor activation. Furthermore, allosteric modulators targeting the CaSR represent a potential therapy for patients with symptomatic forms of FHH and ADH, and their specific actions on distinct signalling pathways may offer a precision medicine approach to treatment. In the last decade, the genetic heterogeneity of FHH and ADH has emerged, with mutations in the Gα11 protein, by which CaSR signals, and the adaptor protein-2 sigma subunit, by which CaSR is endocytosed, being revealed as additional contributors to calcaemic disorders. Studies of these mutations have uncovered novel mechanisms by which CaSR is internalised, and demonstrated that CaSR can signal by an endosomal pathway. Additionally, non-calcitropic roles have emerged for the receptor in inflammation, bronchoconstriction, wound healing, gastro-pancreatic hormone secretion, hypertension, and glucose metabolism. Understanding the mechanisms by which these novel signal pathways and non-calcitropic roles arise are likely to provide continued insights into the CaSR for years to come.

Volume 59

Society for Endocrinology BES 2018

Glasgow, UK
19 Nov 2018 - 21 Nov 2018

Society for Endocrinology 

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