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

Research output: Contribution to journalArticleResearchpeer-review

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.
Original languageEnglish
Pages (from-to)215-225
Number of pages11
JournalTrends in Pharmacological Sciences
Volume36
Issue number4
DOIs
Publication statusPublished - 2015

Keywords

  • allosteric modulator
  • biased signaling
  • calcilytic
  • calcimimetic

Cite this

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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.",
keywords = "allosteric modulator, biased signaling, calcilytic, calcimimetic",
author = "Katie Leach and Conigrave, {Arthur D} and Sexton, {Patrick M} and Arthur Christopoulos",
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Towards tissue-specific pharmacology: insights from the calcium-sensing receptor as a paradigm for GPCR (patho)physiological bias. / Leach, Katie; Conigrave, Arthur D; Sexton, Patrick M; Christopoulos, Arthur.

In: Trends in Pharmacological Sciences, Vol. 36, No. 4, 2015, p. 215-225.

Research output: Contribution to journalArticleResearchpeer-review

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AB - 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.

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