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

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 subjectto 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.