International Union of Basic and Clinical Pharmacology. CVIII. Calcium-Sensing Receptor Nomenclature, Pharmacology, and Function

Abstract

The calcium-sensing receptor (CaSR) is a class C G protein-coupled receptor that responds to multiple endogenous agonists and allosteric modulators, including divalent and trivalent cations, L-amino acids, g-glutamyl peptides, polyamines, polycationic peptides, and protons. The CaSR plays a critical role in extracellular calcium (Ca 2+ o) homeostasis, as demonstrated by the many naturally occurring mutations in the CaSR or its signaling partners that cause Ca 2+ o homeostasis disorders. However, CaSR tissue expression in mammals is broad and includes tissues unrelated to Ca 2+ o homeostasis, in which it, for example, regulates the secretion of digestive hormones, airway constriction, cardiovascular effects, cellular differentiation, and proliferation. Thus, although the CaSR is targeted clinically by the positive allosteric modulators (PAMs) cinacalcet, evocalcet, and etelcalcetide in hyperparathyroidism, it is also a putative therapeutic target in diabetes, asthma, cardiovascular disease, and cancer. The CaSR is somewhat unique in possessing multiple ligand binding sites, including at least five putative sites for the "orthosteric" agonist Ca 2+ o , an allosteric site for endogenous L-amino acids, two further allosteric sites for small molecules and the peptide PAM, etelcalcetide, and additional sites for other cations and anions. The CaSR is promiscuous in its G protein-coupling preferences, and signals via G q/11 , G i/o , potentially G 12/13 , and even G s in some cell types. Not surprisingly, the CaSR is subject to biased agonism, in which distinct ligands preferentially stimulate a subset of the CaSR's possible signaling responses, to the exclusion of others. The CaSR thus serves as a model receptor to study natural bias and allostery. Significance Statement-The calcium-sensing receptor (CaSR) is a complex G protein-coupled receptor that possesses multiple orthosteric and allosteric binding sites, is subject to biased signaling via several different G proteins, and has numerous (patho)physiological roles. Understanding the complexities of CaSR structure, function, and biology will aid future drug discovery efforts seeking to target this receptor for a diversity of diseases. This review summarizes what is known to date regarding key structural, pharmacological, and physiological features of the CaSR.

Keratinocyte-derived microvesicle particles mediate ultraviolet B radiation–induced systemic immunosuppression

“…The selectivity of the CaSR for the keratinocyte is modest, as other epithelial cell types (e.g., renal epithelium) also express this membrane protein (25). Yet in the present studies the increased levels of plasma MVP CaSR expression following UVB in mice (Supplementary Figure 7) and in human subjects (Figure 3 c) undergoing UVB treatments to widespread areas of skin fit with the concept that these MVP are keratinocyte-derived.…”

“…To assess if UVB-MVP can potentially serve this role, we tested if keratinocyte-derived MVPs could be measured in plasma following UVB irradiation of skin. As shown in Figure 2 To confirm the keratinocyte origin of the increased plasma MVPs, we tested the expression of membrane protein calcium-sensing receptor (CaSR), which has been demonstrated to be expressed in keratinocytes and other epithelial tissues (25).…”

Calcium-Sensing Receptor (CaSR), Its Impact on Inflammation and the Consequences on Cardiovascular Health

“…The intracellular signaling by CaSR is expected to occur in different stages ( Figure 1 ). The first stage after receptor activation is the coupling of CaSR to G i/o and G q/11 families of heterotrimeric G proteins that consequently activate signaling pathways [ 16 ]. The phospholipases are also activated, which in turn activate inositol triphosphate (IP 3 ) and diacylglcerol (DAG) pathways.…”

G Protein-Coupled Receptors in Taste Physiology and Pharmacology

“…Because of its pathophysiological importance, various synthetic PAMs and NAMs of CaSR have been identified and are in clinical use. The allosteric modulation of CaSR by synthetic drugs has been recently reviewed ( Hannan et al, 2016 ; Chavez-Abiega et al, 2020 ; Leach et al, 2020 ). Since the 1990’s the term calcimimetics and calcilytics, have been used for drugs that mimic or antagonize the effect of extracellular Ca 2+ on CaSR activity, respectively.…”

“…Nevertheless, subtle differences in ligand–receptor interactions drive negative vs. positive modulation of CaSR signaling, by NPS2143 or cinacalcet and NPSR-568, respectively ( Miedlich et al, 2004 ; Leach et al, 2016 ; Keller et al, 2018 ). The details of CaSR allosteric modulation by synthetic drugs is out of the scope of the current review, for a comprehensive explanation refer to these studies ( Chaves-López et al, 2014 ; Hannan et al, 2016 ; Leach et al, 2020 ).…”