Deciphering biased inverse agonism of cangrelor and ticagrelor at P2Y12 receptor.
Deciphering biased inverse agonism of cangrelor and ticagrelor at P2Y12 receptor.
Cell Mol Life Sci. 2018 Nov 07;:
Authors: Garcia C, Maurel-Ribes A, Nauze M, N'Guyen D, Martinez LO, Payrastre B, Sénard JM, Galés C, Pons V
Abstract
P2Y12 receptor (P2Y12-R) is one of the major targets for drug inhibiting platelet aggregation in the treatment/prevention of arterial thrombosis. However, the clinical use of P2Y12-R antagonists faces some limitations, such as a delayed onset of action (clopidogrel) or adverse effect profile (ticagrelor, cangrelor), justifying the development of a new generation of P2Y12-R antagonists with a better clinical benefit-risk balance. Although the recent concept of biased agonism offers the possibility to alleviate undesirable adverse effects while preserving therapeutic outcomes, it has never been explored at P2Y12-R. For the first time, using highly sensitive BRET2-based probes, we accurately delineated biased ligand efficacy at P2Y12-R in living HEK293T cells on G protein activation and downstream effectors. We demonstrated that P2Y12-R displayed constitutive Gi/o-dependent signaling that is impaired by the R122C mutation, previously associated with a bleeding disorder. More importantly, we reported the biased inverse agonist efficacy of cangrelor and ticagrelor that could underlie their clinical efficacy. Our study points out that constitutive P2Y12-R signaling is a normal feature of the receptor that migh...
Source: Cellular and Molecular Life Sciences : CMLS - Category: Cytology Authors: Garcia C, Maurel-Ribes A, Nauze M, N'Guyen D, Martinez LO, Payrastre B, Sénard JM, Galés C, Pons V Tags: Cell Mol Life Sci Source Type: research