Olfactory Receptors

Small, paired patches of olfactory epithelium, each approximately 2 cm2 in size, are located within the uppermost levels of the nasal cavities (Fig. 1). They are arranged in a horizontal line just below the level of the eyes. Three major cell types are present: olfactory receptor neurons, supporting or sustentacular cells, and basal cells, which are the stem cells for production of new receptor cells. Interspersed among the cells of the olfactory epithelium are Bowman's glands, which produce a layer of mucus covering the nasal lining. The total mucus content is replaced every 10 minutes and is composed primarily of a mucopolysaccharide solution containing enzymes, antibodies, salts, and special proteins that bind odorous substances. Antibodies in the mucus are particularly important because of the presence of viruses and bacteria in aspirated air. If incorporated into olfactory neurons, these disease vectors can gain direct access to brain tissue by being transported within centrally projecting processes of the olfactory neurons. Hanta virus, present in dust from droppings of infected deer mice, is transmitted to humans in this manner.

Odorant binding proteins present within the mucus bind to odorous molecules, acting like molecular sieves that trap and concentrate the substances and facilitate their interaction with olfactory neurons. Through the actions of binding proteins, the operating sensitivity of the olfactory system is significantly enhanced. Humans can sense certain molecules at a concentration of a few parts per trillion, yet individual olfactory receptor neurons respond only to concentrations that are 1000 times greater. Odorant binding proteins are necessary to concentrate these molecules to reach levels that are within the detectable range of individual receptors.

Odorous molecules vary widely in chemical composition and three-dimensional shape. Humans generally recognize 10,000 separate odors; however, with training, individuals such as whiskey blenders or perfumers can increase that number tenfold. Only 20% of all recognizable odors are pleasant. The rest are unpleasant and represent potentially dangerous substances, thus supporting the assumption that the major role of the olfactory

Support Line Array

FIGURE 1 Organization of the olfactory epithelium. (A) Olfactory sensory neurons extend from the paired olfactory epithelial patches, through the cribriform plate into the overlying paired olfactory bulbs. The vomeronasal organ also contains olfactory neurons for pheromone detection and sexual function. (B) Olfactory neurons are embedded in the olfactory epithelium with their odor-sensitive cilia extending into the overlying mucus. They are flanked by supporting cells and basal cells, the latter giving rise to new olfactory neurons. Bowman's glands secrete the mucus that traps and transports airborne chemicals.

FIGURE 1 Organization of the olfactory epithelium. (A) Olfactory sensory neurons extend from the paired olfactory epithelial patches, through the cribriform plate into the overlying paired olfactory bulbs. The vomeronasal organ also contains olfactory neurons for pheromone detection and sexual function. (B) Olfactory neurons are embedded in the olfactory epithelium with their odor-sensitive cilia extending into the overlying mucus. They are flanked by supporting cells and basal cells, the latter giving rise to new olfactory neurons. Bowman's glands secrete the mucus that traps and transports airborne chemicals.

system is to provide a trigger for protective avoidance behavior.

It does not appear that separate binding proteins within the mucus exist for each recognizable odor; rather, a much smaller set of binding proteins is produced, each of which is capable of binding a wide range of odorants. In contrast, the odorant receptor proteins located on membranes of individual receptor cells show a relatively high degree of binding specificity, and it is estimated that more than 1000 distinct types of odorant receptor proteins are produced.

Each neuron produces only one or perhaps very few different types of receptor protein. Sets of odorant-specific neurons are distributed within restricted regions of the olfactory epithelium. Three or more regions have been defined within experimental animals, such as rat, and each region responds to a specified ensemble of odors.

Odorant receptors are members of a receptor super-family, all with seven transmembrane-spanning alpha-helix regions (Fig. 2). They are produced by members of the largest gene family yet described. The visual pigment,

protein

FIGURE 2 Molecular configuration of the olfactory epithelium. Olfactory receptors (shown in blue) are membrane proteins located in the ciliary membrane of olfactory neurons. They are composed of seven membrane-spanning regions and a binding site (white circle) for specific odorants (blue flower). Humans produce about 1000 different receptor proteins, with only one to three types expressed by a given cell. (A) Inactive cilia show a receptor-bound G-protein, called Golf (G-olfactory protein), inactive adenylyl cyclase, and closed cation and chloride channels. (B) When an appropriate odorant binds to the receptor, it activates Golf, which then binds guanosine triphosphate (GTP) and activates adenylyl cyclase to produce cyclic adenosine monophosphate (cAMP). cAMP directly opens cation channels, causing depolarization of the cilia. The entering calcium also opens calcium-sensitive chloride channels. Because of the unusually high levels of intracellular chloride present, chloride leaves the cell, thus causing further depolarization. Depolarization of the cilia spreads to the cell body and leads to action potentials that originate in the initial part of the axon.

protein

FIGURE 2 Molecular configuration of the olfactory epithelium. Olfactory receptors (shown in blue) are membrane proteins located in the ciliary membrane of olfactory neurons. They are composed of seven membrane-spanning regions and a binding site (white circle) for specific odorants (blue flower). Humans produce about 1000 different receptor proteins, with only one to three types expressed by a given cell. (A) Inactive cilia show a receptor-bound G-protein, called Golf (G-olfactory protein), inactive adenylyl cyclase, and closed cation and chloride channels. (B) When an appropriate odorant binds to the receptor, it activates Golf, which then binds guanosine triphosphate (GTP) and activates adenylyl cyclase to produce cyclic adenosine monophosphate (cAMP). cAMP directly opens cation channels, causing depolarization of the cilia. The entering calcium also opens calcium-sensitive chloride channels. Because of the unusually high levels of intracellular chloride present, chloride leaves the cell, thus causing further depolarization. Depolarization of the cilia spreads to the cell body and leads to action potentials that originate in the initial part of the axon.

rhodopsin, is a member of this same superfamily of proteins, and it shares many common attributes with odorant receptors, including its linkage to a G-protein as well as similarities in the general attributes of the associated second-messenger cascade. The specific G-protein in photoreceptors is transducin; in olfactory receptors, it is called Golf (G-protein in olfactory receptors). Binding to the receptor activates Golf, which then stimulates ade-nylate cyclase to produce cyclic adenosine monophosphate (cAMP). Calcium channels in the neuronal membrane bind cAMP and thereby increase their conductance. This leads to calcium influx, calcium activation of chloride channels, depolarization, and generation of a receptor potential that at threshold levels will fire an action potential. In most neurons, increased chloride conductance leads to hyperpolarization, but in olfactory neurons the opposite occurs. This is because olfactory neurons have an unusually high concentration of intra-cellular chloride, and increased chloride conductance will thus cause efflux of the negatively charged chloride and concomitant cell depolarization.

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