G protein-coupled receptors (GPCRs) constitute a central component of cellular signal transduction processes, and are the major pharmaceutical target for a host of human diseases and disorders. However, the underlying molecular mechanisms by which endogenous ligands access the active site are still unclear. We have recently shown for an olfactory receptor, TAAR13c the presence of a second binding site in a vestibule on the external surface, which blocks the passage of the ligand towards the inner binding site. Hence, such ligand-gating mechanism might constitute a regulatory mechanism to determine ligand sensitivity for an entire class of olfactory receptors. Elimination of the external binding site generated supersensitive receptors suggesting this site to act as a gate. We also observed such a gating for another member of taar gene family, Taar13d and for zebrafish serotonergic receptor 5-HTR4 which is the ancestral gene from which the taar gene family originated. Hence, the proposed gating mechanism for olfactory receptors surprisingly exhibits pronounced similarity to processes described for access of binding site for some neurotransmitter receptors.