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

Br J Pharmacol. 2018 Nov;175(21):4083-4094. doi: 10.1111/bph.14086. Epub 2017 Dec 11.

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 α11 (Gα11 ) 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, Gα11 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.

Linked articles: 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Allosteric Regulation / drug effects
  • Amino Alcohols / chemistry
  • Amino Alcohols / pharmacology*
  • Animals
  • Calcimimetic Agents / chemistry
  • Calcimimetic Agents / pharmacology*
  • Humans
  • Receptors, Calcium-Sensing / antagonists & inhibitors*
  • Receptors, Calcium-Sensing / metabolism
  • Signal Transduction / drug effects*

Substances

  • Amino Alcohols
  • Calcimimetic Agents
  • Receptors, Calcium-Sensing