Towards tissue-specific pharmacology: insights from the calcium-sensing receptor as a paradigm for GPCR (patho)physiological bias. (April 2015)

• Record Type: Journal Article
• Authors: Leach, Katie; Conigrave, Arthur D.; Sexton, Patrick M.; Christopoulos, Arthur
• Is Part Of: Trends in pharmacological sciences. Volume 36:Number 4(2015)
• Page Start: 215
• Page End: 225
• Publication Date: 2015-04
• Subjects: biased signaling -- allosteric modulator -- calcimimetic -- calcilytic; Pharmacology -- Periodicals; Pharmacology -- trends -- Periodicals; Pharmacologie -- Périodiques; Pharmacology; Electronic journals; Periodicals; 615.1
• DOI: 10.1016/j.tips.2015.02.004
• Languages: English
• ISSNs: 0165-6147

Abstract

Highlights: Biased (i.e., pathway-specific) signaling is described for GPCRs. Biased signaling arises from distinct receptor conformational states. The calcium-sensing receptor is identified as a paradigm for biased signaling. Biased signaling may permit the design of tissue-specific drugs. 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.