Molecular Basis of Mammalian Odor Discrimination: A Status Report

Abstract

Humans have 396 unique, intact olfactory receptors (ORs), G-protein coupled receptors (GPCRs) containing receptor-specific binding sites; other mammals have more. Activation of these transmembrane proteins by an odorant initiates a signaling cascade, evoking an action potential leading to perception of a smell. Because the number of distinguishable odorants vastly exceeds the number of ORs, research has focused on mechanisms of recognition and signaling processes for classes of odorants. In this review, selected recent examples will be presented of "deorphaned" mammalian receptors, where the OR ligands (odorants) as well as key aspects of receptor-odorant interactions were identified using odorant-mediated receptor activation data together with site-directed mutagenesis and molecular modeling. Based on cumulative evidence from OR deorphaning and olfactory receptor neuron activation studies, a receptor-ligand docking model rather than an alternative bond vibration model is suggested to best explain the molecular basis of the exquisitely sensitive odor discrimination in mammals.

Keywords: G-protein coupled receptor (GPCR); docking model of olfaction; molecular dynamics (MD); molecular modeling (MM); odorants; olfactory bulb (OB); olfactory epithelium (OE); olfactory receptor (OR); olfactory receptor neuron (ORN); saturation transfer difference nuclear magnetic resonance (STD-NMR); site-directed mutagenesis; smell; vibration theory of olfaction (VTO).