Calcimimetic and calcilytic therapies for inherited disorders of the calcium-sensing receptor signalling pathway

Hannan, Fadil M ORCID: 0000-0002-2975-5170, Olesen, Mie K ORCID: 0000-0003-0338-5690 and Thakker, Rajesh V (2018) Calcimimetic and calcilytic therapies for inherited disorders of the calcium-sensing receptor signalling pathway. BRITISH JOURNAL OF PHARMACOLOGY, 175 (21). pp. 4083-4094.

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Official URL: http://dx.doi.org/10.1111/bph.14086

Abstract

The calcium-sensing receptor (CaS receptor) plays a pivotal role in extracellular calcium homeostasis, and germline loss-of-function and gain-of-function mutations cause familial hypocalciuric hypercalcaemia (FHH) and autosomal dominant hypocalcaemia (ADH), respectively. CaS receptor signal transduction in the parathyroid glands is probably regulated by G-protein subunit α<sub>11</sub> (Gα<sub>11</sub> ) and adaptor-related protein complex-2 σ-subunit (AP2σ), and recent studies have identified germline mutations of these proteins as a cause of FHH and/or ADH. Calcimimetics and calcilytics are positive and negative allosteric modulators of the CaS receptor that have potential efficacy for symptomatic forms of FHH and ADH. Cellular studies have demonstrated that these compounds correct signalling and/or trafficking defects caused by mutant CaS receptor, Gα<sub>11</sub> or AP2σ proteins. Moreover, mouse model studies indicate that calcilytics can rectify the hypocalcaemia and hypercalciuria associated with ADH, and patient-based studies reveal calcimimetics to ameliorate symptomatic hypercalcaemia caused by FHH. Thus, calcimimetics and calcilytics represent targeted therapies for inherited disorders of the CaS receptor signalling pathway.<h4>Linked articles</h4>This article is part of a themed section on Molecular Pharmacology of GPCRs. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.21/issuetoc.

Item Type:	Article
Uncontrolled Keywords:	Animals, Humans, Amino Alcohols, Receptors, Calcium-Sensing, Signal Transduction, Allosteric Regulation, Calcimimetic Agents
Depositing User:	Symplectic Admin
Date Deposited:	21 Nov 2017 07:36
Last Modified:	19 Jan 2023 06:50
DOI:	10.1111/bph.14086
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3012585