title: Towards tissue-specific pharmacology: insights from the calcium-sensing receptor as a paradigm for GPCR (patho)physiological bias.
abstract: The calcium-sensing receptor (CaSR) is a widely expressed G protein-coupled receptor (GPCR) that mediates numerous tissue-specific functions. Its multiple ligands and diverse roles attest to the need for exquisite control over the signaling pathways that mediate its effects. 'Biased signaling' is the phenomenon by which distinct ligands stabilize preferred receptor signaling states. The CaSR is subject to biased signaling in response to its endogenous ligands. Interestingly, the 'natural' bias of the CaSR is altered in disease states, and small molecule drugs engender biased allosteric modulation of downstream signaling pathways. Thus, biased signaling from the CaSR also has important implications pathophysiologically and therapeutically. As outlined in this review, this novel paradigm extends to other GPCRs, making the CaSR a model for studies of ligand-biased signaling and for understanding how it may be used to foster selective drug activity in different tissues.
authors.affiliation: Monash Institute of Pharmaceutical Sciences, 381 Royal Parade, Parkville VIC, Australia. Electronic address: katie.leach@monash.edu.
authors.forename: Katie
authors.initials: K
authors.lastname: Leach
authors.affiliation: School of Molecular Bioscience, Charles Perkins Centre, University of Sydney, NSW 2006, Australia.
authors.forename: Arthur D
authors.initials: AD
authors.lastname: Conigrave
authors.affiliation: Monash Institute of Pharmaceutical Sciences, 381 Royal Parade, Parkville VIC, Australia.
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Sexton
authors.affiliation: Monash Institute of Pharmaceutical Sciences, 381 Royal Parade, Parkville VIC, Australia.
authors.forename: Arthur
authors.initials: A
authors.lastname: Christopoulos
mesh_terms: D000818:Animals; D015195:Drug Design; D006801:Humans; D008024:Ligands; D011485:Protein Binding / Q000502:physiology; D017433:Protein Structure, Secondary; D044169:Receptors, Calcium-Sensing / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014018:Tissue Distribution / Q000502:physiology
chemical_list: D008024:Ligands; D044169:Receptors, Calcium-Sensing; D043562:Receptors, G-Protein-Coupled
keywords: allosteric modulator; biased signaling; calcilytic; calcimimetic