G protein-coupled receptors (GPCR) constitute a large superfamily of cell-membrane proteins that function to communicate extracellular signals into the cell. As such, they are classical endocrine receptors. Over the past decades, our understanding of GPCRs as simple switches, which are coupled to various G-proteins and which determine their signaling behavior, has matured to appreciate them as quite sophisticated switchboards, interacting with numerous additional proteins or even as biological microprocessors (1, 2). The signals or the information that these GPCR process cover a fascinating spectrum of ligands and molecules and range for example from tiny photons, via less tiny protons, to ions, lipids, amino acids, peptides, proteins, and manmade materials, i.e. drugs. The functions of these ligands at their receptors can be broadly grouped into agonists, antagonists, inverse agonists, and allosteric modulators (3). For the latter group of molecules, subclassifications into agoallosteric modulators, allosteric agonists, and allosteric enhancers have been proposed (4). Hence, the molecular and tissue context of the receptor along with the nature of the external signal determine the processing of the signal into distinct intracellular pathway effects. In other words, when a GPCR receives some news, it translates this into cell-specific views. The calcium-sensing receptor (CaR), as a member of class C GPCR, has been the subject of intense research and hypothesis testing with regard to its molecular functioning, its role in different tissues, and subsequently as a drug target in humans since its discovery in 1993 (5). Although the primary physiological function of the CaR involves the tight regulation of extracellular Ca via CaR located in the kidney and parathyroid glands (in concert with other endocrine molecules such as PTH, calcitonin, or 1,25-dihydroxyvitamin D3) (6), additional physiological functions are likely to exist in vivo, e.g. in bone development, mineralization, and turnover (7, 8). Two classes of allosteric CaR modulators for therapeutic application have attracted the most interest; they are broadly coined calcimimetics and calcilytics (9). Although the calcimimetic cinacalcet HCL has been successfully introduced into many markets as a treatment for secondary hyperparathyroidism in chronic renal failure and parathyroid carcinoma, approval of an indication for a calcilytic compound has not been achieved to date (10, 11). One of the reasons for the difficulties in bringing a calcilytic to the market might be linked to insufficient tissue selectivity causing untoward side effects. In the current issue of Endocrinology, Davey et al. (12) report on their findings of a series of simple, yet elegant experiments to characterize biased signaling at the CaR via positive and negative allosteric modulators. They do this by determining the effects of the calcimimetics, NPSR568 or cinacalcet, and the calcilytic, NPS-2143, on Ca o-mediated intracellular Ca 2 mobilization, ERK1/2 phosphorylation, and plasma membrane ruffling in a stably transfected human embryonic kidney 293-TREx cmyc-CaSR cell line. As a result, quantification of the allosteric effects of these molecules on Ca o-mediated signaling across the mentioned pathway representatives demonstrates that these ligands promote stimulus bias at the CaR, reflecting differential stabilization of distinct affinity states of the receptor or differential cooperativity between the allosteric modulator and Ca o. Why is this important? Because it contributes to our understanding of molecular selectivity phenomena and thereby directly links to tackling tissue specificity or pathway specificity as one of the goals of optimizing structure-
Search from 250 M+ research papersSearch from 250 M+ research papers
Open Access
Sep 7, 2023
Mayra Michelle Nuñez Rueda + 2
