Biased allosteric modulation at the CaS receptor engendered by structurally diverse calcimimetics

Cook, A.E. and Mistry, S.N. and Gregory, K.J. and Furness, S.G.B. and Sexton, P.M. and Scammells, P.J. and Conigrave, A.D. and Christopoulos, A. and Leach, K. (2014) Biased allosteric modulation at the CaS receptor engendered by structurally diverse calcimimetics. British Journal of Pharmacology, 172 (1). pp. 185-200. ISSN 1476-5381

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Abstract

Background and Purpose

Clinical use of cinacalcet in hyperparathyroidism is complicated by its tendency to induce hypocalcaemia, arising partly from activation of calcium-sensing receptors (CaS receptors) in the thyroid and stimulation of calcitonin release. CaS receptor allosteric modulators that selectively bias signalling towards pathways that mediate desired effects [e.g. parathyroid hormone (PTH) suppression] rather than those mediating undesirable effects (e.g. elevated serum calcitonin), may offer better therapies.

Experimental Approach

We characterized the ligand-biased profile of novel calcimimetics in HEK293 cells stably expressing human CaS receptors, by monitoring intracellular calcium (Ca2+i) mobilization, inositol phosphate (IP)1 accumulation, ERK1/2 phosphorylation (pERK1/2) and receptor expression.

Key Results

Phenylalkylamine calcimimetics were biased towards allosteric modulation of Ca2+i mobilization and IP1 accumulation. S,R-calcimimetic B was biased only towards IP1 accumulation. R,R-calcimimetic B and AC-265347 were biased towards IP1 accumulation and pERK1/2. Nor-calcimimetic B was unbiased. In contrast to phenylalkylamines and calcimimetic B analogues, AC-265347 did not promote trafficking of a loss-of-expression, naturally occurring, CaS receptor mutation (G670E).

Conclusions and Implications

The ability of R,R-calcimimetic B and AC-265347 to bias signalling towards pERK1/2 and IP1 accumulation may explain their suppression of PTH levels in vivo at concentrations that have no effect on serum calcitonin levels. The demonstration that AC-265347 promotes CaS receptor receptor signalling, but not trafficking reveals a novel profile of ligand-biased modulation at CaS receptors The identification of allosteric modulators that bias CaS receptor signalling towards distinct intracellular pathways provides an opportunity to develop desirable biased signalling profiles in vivo for mediating selective physiological responses.

Item Type: Article
Additional Information: This is the peer reviewed version of the following article: Cook, A. E., Mistry, S. N., Gregory, K. J., Furness, S. G. B., Sexton, P. M., Scammells, P. J., Conigrave, A. D., Christopoulos, A. and Leach, K. (2015), Biased allosteric modulation at the CaS receptor engendered by structurally diverse calcimimetics. British Journal of Pharmacology, 172: 185–200,which has been published in final form at http://dx.doi.org/10.1111/bph.12937. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.
Schools/Departments: University of Nottingham UK Campus > Faculty of Science > School of Pharmacy
Identification Number: https://doi.org/10.1111/bph.12937
Depositing User: Mistry, Dr Shailesh
Date Deposited: 09 Oct 2015 10:52
Last Modified: 16 Sep 2016 01:21
URI: http://eprints.nottingham.ac.uk/id/eprint/30313

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