The potential for biased signalling in the P2Y receptor family of GPCRs

The purinergic receptor family is primarily activated by nucleotides, and contains members of both the G protein coupled-receptor (GPCR) superfamily (P1 and P2Y) and ligand-gated ion channels (P2X). The P2Y receptors are widely expressed in the human body, and given the ubiquitous nature of nucleotides, purinergic signalling is involved with a plethora of molecular physiological functions. The widespread nature of P2Y receptors make them a viable therapeutic target, but with the negative risk of on-target side effects. Some of the side effects associated with P1 and P2Y receptors arise due to the pleiotropic nature of many GPCRs, because a singular GPCR can activate several G proteins, as well as recruit β-arrestins. The utilisation of ligands that exhibit downstream pathway-specific activation, also known as biased signalling, at the P2Y receptors could circumvent these issues. This review will cover the signalling nature and impact of the P2Y family, with an emphasis on individual activity patterns of the P2Y receptors. This review also discusses current literature on the development of biased ligands for these receptors, with an aim to highlight the most beneficial targets and outcomes.