The differential signalling of the succinate receptor SUCNR1/GPR91, through Gi versus Gq

Abstract: G protein-coupled receptors are the biggest family of membrane bound receptor in the human genome, they are also target for many drugs due to their accessible location in the cell membrane. We have characterized the G protein recruitment of the succinate receptor 1 (SUCNR1/GPR91). GPR91 was deorphanized in 2004 and already then it was suggested that GPR91 could couple to the Gi-family and the Gq-family of G proteins. Since then, the fact that it could do this have been debated. We have used and optimized the TRUPATH biosensor (Olsen et al., 2020) to show dose-response recruitment curves for both hGPR91 and mGPR91 for the Gi- and Gq-family of G proteins. We show that hGPR91 recruits all tested α-subunits of the Gi- and Gq-family whilst mGPR91 recruits all except for αQ. We also show that mGPR91 is approximately 1 order more potent than hGPR91. We conclude that the TRUPATH biosensor is a good tool for investigation of G protein recruitment, but it needs to be optimized to fit each receptor that should be investigated. Further on we suggest using the results obtained as a guide for further investigation of GPR91 structurally as well as to see if there is any bias signalling occurring.