# Exploring bias in platelet P2Y1 signalling: Host defence versus haemostasis

## TL;DR

The paper explores how platelet P2Y1 signaling differs in inflammation versus blood clotting, suggesting potential for targeted therapies.

## Contribution

The paper highlights distinct signaling pathways of P2Y1 in inflammation versus haemostasis, suggesting biased agonism possibilities.

## Key findings

- P2Y1 signaling via Rho-GTPase is crucial during inflammation without affecting haemostasis.
- ADP activates P2Y1 for thrombi formation during haemostasis.
- Biased agonism from endogenous nucleotides may offer therapeutic control of platelet function.

## Abstract

Platelets are necessary for maintaining haemostasis. Separately, platelets are important for the propagation of inflammation during the host immune response against infection. The activation of platelets also causes inappropriate inflammation in various disease pathologies, often in the absence of changes to haemostasis. The separate functions of platelets during inflammation compared with haemostasis are therefore varied and this will be reflected in distinct pathways of activation. The activation of platelets by the nucleotide adenosine diphosphate (ADP) acting on P2Y1 and P2Y12 receptors is important for the development of platelet thrombi during haemostasis. However, P2Y1 stimulation of platelets is also important during the inflammatory response and paradoxically in scenarios where no changes to haemostasis and platelet aggregation occur. In these events, Rho‐GTPase signalling, rather than the canonical phospholipase Cβ (PLCβ) signalling pathway, is necessary. We describe our current understanding of these differences, reflecting on recent advances in knowledge of P2Y1 structure, and the possibility of biased agonism occurring from activation via other endogenous nucleotides compared with ADP. Knowledge arising from these different pathways of P2Y1 stimulation of platelets during inflammation compared with haemostasis may help therapeutic control of platelet function during inflammation or infection, while preserving essential haemostasis.

This article is part of a themed issue on Platelet purinergic receptor and non‐thrombotic disease. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v181.4/issuetoc