Physiopathology of nasal and ecnomotopic olfactory receptors: focus on molecular pathways and potential pharmacological modulation.

Detection and discrimination of chemosensory stimuli (usually known as odorants) by the olfactory system exert a crucial role in animal survival. Olfactory receptors (ORs) are a large family of G protein-coupled receptors (GPCRs) mainly expressed by the main olfactory neuroepithelium (OE) at the nasal level and can sense different odorants affecting the electric activity of olfactory sensory neurons (OSNs) eventually generating the sense of smell. Recent evidence suggests that the olfactory mucosa, namely, the OE plus the olfactory mucus, plays a critical role as an immune barrier. Healthy olfactory pathways need intact function and anatomy within the nose itself, the OE, the olfactory bulb, and the central brain structures in charge of olfactory processing. Olfactory loss influences nutrition, safety, and social relationships, and subjects with olfactory impairment have been revealed to be at greater risk for overall mortality. Of note, ORs are not only expressed within the OE but an ecnomotopic expression has also been identified, serving different physiological functions, such as glucose and lipid metabolism and wound healing. It should be noted that ligands of ecnomotopic ORs may originate from naturally occurring or synthetic odor compounds present in the foods and/or food additives, as well as from endogenous compounds produced by host and/or microbiome cells. This review summarizes the anatomy, physiology, and immunology of the human olfactory system. Then, it delves into the ecnomotopic OR expression and signaling pathways. Finally, it reports recent data highlighting how the OR expression can be modulated offering guidance and future directions for clinical translatability.