Behind the Curtain: Cellular Mechanisms for Allosteric Modulation of Calcium-sensing Receptors

Overview

Journal Br J Pharmacol

Publisher Wiley

Specialty Pharmacology

Date 2011 Apr 8

PMID 21470201

Citations 13

Authors

Alice Cavanaugh

Ying Huang

Gerda E Breitwieser

Affiliations

Soon will be listed here.

Abstract

Calcium-sensing receptors (CaSR) are integral to regulation of systemic Ca(2+) homeostasis. Altered expression levels or mutations in CaSR cause Ca(2+) handling diseases. CaSR is regulated by both endogenous allosteric modulators and allosteric drugs, including the first Food and Drug Administration-approved allosteric agonist, Cinacalcet HCl (Sensipar®). Recent studies suggest that allosteric modulators not only alter function of plasma membrane-localized CaSR, but regulate CaSR stability at the endoplasmic reticulum. This brief review summarizes our current understanding of the role of membrane-permeant allosteric agonists in cotranslational stabilization of CaSR, and highlights additional, indirect, signalling-dependent role(s) for membrane-impermeant allosteric drugs. Overall, these studies suggest that allosteric drugs act at multiple cellular organelles to control receptor abundance and hence function, and that drug hydrophobicity can bias the relative contributions of plasma membrane and intracellular organelles to CaSR abundance and signalling.

Citing Articles

Identification and characterization of a novel CASR mutation causing familial hypocalciuric hypercalcemia.

Lin C, Ding Y, Huang S, Chen Y, Lee H, Sung C Front Endocrinol (Lausanne). 2024; 15:1291160.

PMID: 38487341 PMC: 10937390. DOI: 10.3389/fendo.2024.1291160.

Ex Vivo Intact Tissue Analysis Reveals Alternative Calcium-sensing Behaviors in Parathyroid Adenomas.

Koh J, Zhang R, Roman S, Duh Q, Gosnell J, Shen W J Clin Endocrinol Metab. 2021; 106(11):3168-3183.

PMID: 34272844 PMC: 8530711. DOI: 10.1210/clinem/dgab524.

Leveraging allostery to improve G protein-coupled receptor (GPCR)-directed therapeutics: cannabinoid receptor 1 as discovery target.

Janero D, Thakur G Expert Opin Drug Discov. 2016; 11(12):1223-1237.

PMID: 27712124 PMC: 6108444. DOI: 10.1080/17460441.2016.1245289.

Calcium Sensing Receptor as a Novel Mediator of Adipose Tissue Dysfunction: Mechanisms and Potential Clinical Implications.

Bravo-Sagua R, Mattar P, Diaz X, Lavandero S, Cifuentes M Front Physiol. 2016; 7:395.

PMID: 27660614 PMC: 5014866. DOI: 10.3389/fphys.2016.00395.

Receptor antagonism/agonism can be uncoupled from pharmacoperone activity.

Janovick J, Spicer T, Smith E, Bannister T, Kenakin T, Scampavia L Mol Cell Endocrinol. 2016; 434:176-85.

PMID: 27389877 PMC: 4983495. DOI: 10.1016/j.mce.2016.07.003.

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