An olfactory receptor neuron (ORN), also called an olfactory sensory neuron (OSN), is a sensory neuron within the olfactory system. ORNs are the principal neurons of the sense of smell: they detect volatile chemicals in inhaled air and convert that chemical signal into an electrical one that is relayed to the olfactory bulb of the brain. Unusually for neurons, ORNs are continually replaced throughout life from stem cells in the olfactory epithelium.
Molecular discovery A major advance in the molecular study of olfaction came in 1991, when Linda Buck and Richard Axel identified a large multigene family that they proposed encodes the odorant receptors, providing the first molecular handle on how ORNs detect odors. Buck and Axel received the 2004 Nobel Prize in Physiology or Medicine for their discoveries concerning odorant receptors and the organization of the olfactory system.
Structure Humans have between 10 and 20 million olfactory receptor neurons (ORNs). In vertebrates, ORNs are bipolar neurons within the pseudostratified olfactory epithelium of the nasal cavity. Each mature neuron extends a short apical dendrite to the epithelial surface, where it ends in a knob bearing non-motile cilia within the mucus. A slender unmyelinated axon extends from the basal pole, joins the olfactory nerve and passes through the cribriform foramina of the cribriform plate before terminating in a glomerulus of the olfactory bulb. The olfactory epithelium contains sustentacular cells (supporting cells), which span the epithelium and support the ORNs, and basal cells near the basement membrane that act as progenitors. The olfactory glands (glands of Bowman) lie in the underlying lamina propria and secrete the mucus bathing the cilia through ducts that open onto the epithelial surface. Many tiny hair-like non-motile cilia protrude from the olfactory receptor cell's dendrites. The dendrites extend to the olfactory epithelial surface and each ends in a dendritic knob from which around 20 to 35 cilia protrude. The cilia have a length of up to 100 micrometers and with the cilia from other dendrites form a meshwork in the olfactory mucus. The ORN dendrite integrates the receptor currents generated across these cilia. The ciliary membrane contains olfactory receptors, a family of G protein-coupled receptors. Many separate olfactory receptor cells express ORs that bind the same set of odors, and the axons of mature canonical ORNs expressing the same receptor converge onto corresponding glomeruli in the olfactory bulb. Mature canonical ORNs generally express one allele of one OR gene. Chromatin-mediated silencing, enhancer interactions and receptor-dependent feedback help establish and stabilize this singular receptor choice. Because each OR recognizes multiple odorants and each odorant activates multiple ORs, the identity of an odor is encoded by the combination of receptors it activates. The orderly convergence of same-receptor axons onto dedicated glomeruli preserves this receptor information as a spatial map in the olfactory bulb.
Regeneration Unlike most neurons, ORNs are continuously replaced throughout life. New ORNs are generated from globose basal cells in the olfactory epithelium, while horizontal basal cells act as a reserve stem-cell pool that is recruited after injury. Turnover is heterogeneous: some neurons are relatively short-lived, whereas mature neurons can persist for months, and the production of replacement neurons increases substantially after epithelial injury. Odorant-receptor gene expression begins as newly generated ORNs differentiate and mature, as demonstrated during olfactory-neuron regeneration in the catfish and characterized during maturation in mice. This lifelong neurogenesis is unusual among mammalian neurons and allows the olfactory epithelium to recover from environmental damage.
Function In vertebrate ORNs, odorant receptors are G protein-coupled receptors located mainly in the membrane of the olfactory cilia. There are approximately 1000 different genes that code for the ORs in the mouse, making them the largest gene family in the mammalian genome; humans have roughly 400 functional OR genes, the remainder having become pseudogenes. An odorant dissolves into the mucus of the olfactory epithelium and binds to an OR. Individual ORs can respond to multiple odorants, and a single odorant can activate multiple ORs, producing a combinatorial receptor code. Odorant binding activates the G protein Golf; its α-subunit, encoded by GNAL, stimulates adenylyl cyclase type III (ACIII) to produce cyclic AMP (cAMP). cAMP opens cyclic nucleotide-gated (CNG) channels, admitting Na+ and Ca2+. The rise in intracellular Ca2+ opens calcium-activated chloride channels, including TMEM16B/ANO2, and because olfactory neurons maintain a high internal chloride concentration, Cl− flows out of the cell, amplifying the depolarization and promoting action potential firing. The main olfactory epithelium also expresses smaller, distinct families of chemosensory receptors in subsets of neurons. Trace amine-associated receptors (TAARs) form a second class of receptors in the olfactory epithelium that detect volatile amines. Distinct from the ORNs of the main olfactory epithelium, the vomeronasal organ (accessory olfactory system) of many vertebrates contains its own sensory neurons expressing unrelated families of putative pheromone receptors.
Desensitization The olfactory receptor neuron has a fast working negative feedback response upon depolarization. When the neuron is depolarizing, the CNG ion channel is open allowing sodium and calcium to rush into the cell. Calcium entering through the CNG channels then promotes adaptation through several feedback pathways. Ca2+ binds to calmodulin, and the resulting Ca2+–calmodulin complex reduces the sensitivity of the CNG channel, limiting further sodium and calcium influx. CaMKII, activated by Ca2+–calmodulin, can phosphorylate ACIII and reduce cAMP production, while phosphodiesterases degrade cAMP. Together these mechanisms reduce the neuron's responsiveness during sustained or repeated stimulation.
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