Agonist-Independent GPCR Activity Regulates Anterior-Posterior Targeting of Olfactory Sensory Neurons

G-protein-coupled receptors (GPCRs) are known to possess two different conformations, active and inactive, and they spontaneously alternate between the two in the absence of ligands. Here, we analyzed the agonist-independent GPCR activity for its possible role in receptor-instructed axonal projection. We generated transgenic mice expressing activity mutants of the β2-adrenergic receptor, a well-characterized GPCR with the highest homology to odorant receptors (ORs). We found that mutants with altered agonist-independent activity changed the transcription levels of axon-targeting molecules—e.g., Neuropilin-1 and Plexin-A1—but not of glomerular segregation molecules—e.g., Kirrel2 and Kirrel3—thus causing shifts in glomerular locations along the anterior-posterior (A-P) axis. Knockout and in vitro experiments demonstrated that Gs, but not Golf, is responsible for mediating the agonist-independent GPCR activity. We conclude that the equilibrium of conformational transitions set by each OR is the major determinant of expression levels of A-P-targeting molecules. [Display omitted] •Agonist-independent GPCR activity regulates A-P targeting of OSN axons•Receptor mutants with altered baseline activity caused shifts in glomerular locations•A stimulatory G protein (Gs), but not Golf, mediates the OR baseline activity•This is a demonstration of in vivo function of GPCR basal activity during development The level of agonist-independent activity of a given olfactory receptor is the major determinant of the expression levels of the anterior-posterior targeting molecules that control axon guidance of olfactory sensory neurons.