Physiological bias governs neutrophil inflammatory threat perception

Background and Purpose The functional G protein-coupled receptor (GPCR) signalling unit consists of an agonist acting on a receptor that is coupled to a G protein that transduces the signals to effectors within a complex cellular environment. While much attention is given to GPCR-agonist or GPCR-transducer relationships, the contribution of the cellular environment remains significantly unexplored. Experimental Approach Here, we juxtaposed the signalling responses triggered by the activation of two GPCR pattern recognition receptors, Formyl peptide receptor 1 and Formyl peptide receptor 2, in a recombinant cell system against their signalling dynamics in the native neutrophilic environment. Key results We observed that agonist activation leads to cell context-dependent substantial differences in the receptor signalling texture. While the impact of receptor activation on de novo cAMP formation varied depending on the cell type, MAPK activation was similar in both systems. This physiological bias was conserved across species. Expression analysis unveiled the absence of the Gαi-sensitive adenylyl cyclases ADCY5 and ADCY6 in neutrophils, implying that cAMP de novo synthesis cannot be inhibited by Gαi-coupled receptors. The signalling behaviour of the Gαi-coupled LTB4 high-affinity receptor BLT1 in neutrophils corroborated our findings. Conclusion and Implications Our data underscore the profound impact of the specific cellular environment on GPCR signalling, causing physiological bias in GPCR signalling, thereby affecting drug efficacy and therapeutic targeting. ### Competing Interest Statement The authors have declared no competing interest.