Biased agonism: a novel paradigm in G protein-coupled receptor signaling observed in acquired hypocalciuric hypercalcemia [Review]

Abstract

Abstract. The classical model of G protein-coupled receptor (GPCR) activation is the two-state model, in which the GPCR exists in equilibrium between an active and inactive state. Based on this model, GPCR ligands have been classified as agonists, inverse agonists, or antagonists depending on their actions in shifting this equilibrium. Recently, however, accumulating evidence has indicated that GPCRs may exist in multiple active and inactive conformational states. In this situation, each ligand recognizes and stabilizes a specific conformation of the GPCR, leading to a set of specific biological effects. Based on this new model, a unique agonist or a combination of the usual agonist and an allosteric modulator may enable activation of a specific signaling pathway via a GPCR that activates multiple signals (biased agonism, functional selectivity). The calcium-sensing receptor autoantibody that we have identified in the serum of a patient with acquired hypocalciuric hypercalcemia (AHH) is the first example of a biased allosteric modulator of a GPCR working in a pathophysiological context. Our findings may indicate the presence of physiological allosteric modulators and provide new directions for the future drug development.

Cinacalcet corrects biased allosteric modulation of CaSR by AHH autoantibody

“…We assessed a male patient with hypercalcemia and hypocalciuria, who was clinically diagnosed as having AHH ( Figure 1A We then evaluated how the patient's autoantibodies would affect the CaSR signaling pathway. Interestingly, we observed that the patient's autoantibodies work as biased allosteric modulators of CaSR, in a manner that we had reported previously (29,31). The patient IgG paradoxically potentiated the CaSR-mediated accumulation of IP, while inhibiting the CaSR-mediated phosphorylation of ERK1/2 (Figure 2A).…”

“…Recently, Pallais et al have also described a patient whose autoantibodies attenuated ERK1/2 phosphorylation but showed no effect against inositol phosphate (IP) accumulation (32). Taken together, these findings suggest that, not only Gq/11 (19,(33)(34)(35), but also Gi/o (19,29,31), is likely to play an important role in CaSR signaling.…”

“…Inactivating autoantibodies directed against CaSR cause acquired hypocalciuric hypercalcemia (AHH) (27)(28)(29), which was first described by Pallais et al (30). In a case of AHH, we subsequently found unique autoantibodies that operate as biased allosteric modulators of CaSR, thereby augmenting Gq/IP signaling pathway and yet attenuating the Gi/ERK1/2 signaling pathway (29,31). Recently, Pallais et al have also described a patient whose autoantibodies attenuated ERK1/2 phosphorylation but showed no effect against inositol phosphate (IP) accumulation (32).…”

Inverse agonism: the classic concept of GPCRs revisited [Review]

“…In the classical two-state model of GPCR activation, GPCRs are considered to exist in equilibrium between an inactive state and an active state [1,7] (Fig. 1).…”

“…1 and 2). However, several lines of evidence lend support to a multi-state model for GPCRs, in which these receptors can spontaneously adopt multiple active and inactive conformational states [7][8][9][10][11]. In this new model, each ligand is hypothesized to recognize and stabilize a specific conformation of each type of GPCR, leading to a set of unique and specific biological effects.…”