The perception of volatile airborne chemicals imposes different demands than the perception of light, sound, touch, or taste. Light is sensed by only four rhodopsin molecules, tuned to different wavelengths. Sound is detected by mechanical effects through hairs that are tuned to different wavelengths. Touch and pain requires a small number of different gated ion channels. The sense of taste measures a small number of substances dissolved in water. In contrast to all these other senses, olfactory systems can discriminate between many hundreds of volatile molecules moving through air. Discrimination between a large number of chemicals is useful in finding food or a mate, sensing pheromones, and avoiding predators, toxins, and fires. Olfactory receptors work with enormous sensitivity. Male moths, for example, can detect single molecules of the signals sent drifting through the air by females. In order to cope with so many signals, the olfactory system employs a large family of olfactory receptor proteins. Humans have about 700 olfactory receptor genes, of which about half are functional (the rest are unproductive pseudogenes), a remarkably large proportion of the estimated 20,000 human genes. Mice are more efficient, with more than 1200 olfactory receptor genes, of which about 800 are functional. That means 3 percent of the mouse genome is composed of olfactory receptor genes. Drosophila has about 60 olfactory receptor genes. In this section we will examine how olfactory receptor genes are employed, and how the brain can recognize which odor has been sensed—the initial stages of interpretation of our chemical world. Odor molecules are called odorants. They have diverse chemical structures, so olfactory receptors face some of the same challenges faced by antibodies and hormone receptors—the need to bind and distinguish many variants of relatively small molecules.

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Olfactory receptors are seven-transmembrane-domain proteins (Figure 22-36). In mammals, olfactory receptors are produced by cells of the nasal epithelium. These cells, called olfactory receptor neurons (ORNs), transduce the chemical signal into action potentials. Each ORN extends a single dendrite to the luminal surface of the epithelium, from which immotile cilia extend to bind inhaled odorants from the air (Figure 22-37a). These olfactory sensory cilia are enriched in the odorant receptors and signal transduction proteins that mediate the initial transduction events. In Drosophila, ORNs have similar structures and are located in the antennae (Figure 22-37b).

In both mammals and Drosophila the ORNs project their axons to the next higher level of the nervous system, which in mammals is located in the olfactory bulb of the brain. The ORN axons synapse with dendrites from mitral neurons in mammals (called projection neurons in insects); these synapses occur in the clusters of synaptic structures called glomeruli. The mitral neurons connect to higher olfactory centers in the brain (Figure 22-38).

Despite the vast number of olfactory receptors, all generate the same intracellular signals through activation of the same trimeric G protein: G_αolf · G_βγ (see Figure 22-36). G_αolf is expressed mainly in olfactory neurons. Like G_αs, the active G_αolf · GTP formed after ligand binding activates an adenylyl cyclase that leads to the production of cyclic AMP (cAMP; see Figure 15-25). Two downstream signaling pathways are activated by cAMP. It binds to a site on the cytosolic face of a cyclic nucleotide–gated (CNG) Na⁺/Ca²⁺ channel, opening the channel and leading to an influx of Na⁺ and Ca²⁺and local depolarization of the cell membrane. This odorant-induced depolarization in the olfactory dendrites spreads throughout the neuronal membrane, resulting in opening of voltage-gated Na⁺ channels in the axon hillock and the generation of action potentials. Molecules of cAMP also activate protein kinase A (PKA), which phosphorylates and thus regulates transcription factors and other intracellular proteins.