International union of basic and clinical pharmacology. CVIII. Calcium-sensing receptor nomenclature, pharmacology, and function
| Autor: | Arthur D. Conigrave, Thor C. Møller, Hans Bräuner-Osborne, Andrew N. Keller, Daniela Riccardi, Katie Leach, Donald T. Ward, Enikö Kállay, Fadil M. Hannan, Rebecca S. Mason, Tracy M. Josephs, Rajesh V. Thakker |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Models
Molecular 0301 basic medicine Agonist G protein medicine.drug_class Allosteric regulation Article Small Molecule Libraries 03 medical and health sciences 0302 clinical medicine GTP-Binding Proteins Small Molecule Libraries/pharmacology medicine Functional selectivity Animals Humans Receptor Pharmacology Binding Sites Drug discovery Chemistry 3. Good health Cell biology 030104 developmental biology Receptors Calcium-Sensing/agonists Molecular Medicine GTP-Binding Proteins/metabolism Signal transduction Calcium-sensing receptor Receptors Calcium-Sensing 030217 neurology & neurosurgery Signal Transduction |
| Zdroj: | Leach, K, Hannan, F M, Josephs, T M, Keller, A N, Møller, T C, Ward, D T, Kallay, E, Mason, R S, Thakker, R V, Riccardi, D, Conigrave, A D & Bräuner-Osborne, H 2020, ' International Union of Basic and Clinical Pharmacology. CVIII. Calcium-Sensing Receptor Nomenclature, Pharmacology, and Function ', Pharmacological Reviews, vol. 72, no. 3, pp. 558-604 . https://doi.org/10.1124/pr.119.018531 Pharmacological Reviews Pharmacol Rev |
| DOI: | 10.1124/pr.119.018531 |
| Popis: | 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, γ-glutamyl peptides, polyamines, polycationic peptides, and protons. The CaSR plays a critical role in extracellular calcium (Ca2+ o) homeostasis, as demonstrated by the many naturally occurring mutations in the CaSR or its signaling partners that cause Ca2+ o homeostasis disorders. However, CaSR tissue expression in mammals is broad and includes tissues unrelated to Ca2+ 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 Ca2+ 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 Gq/11, Gi/o, potentially G12/13, and even Gs 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. |
| Databáze: | OpenAIRE |
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