The Search for Odorant Receptors Commentary

Summary The mammalian olfactory system can recognize and discriminate a large number of different odorant mole- cules. The detection of chemically distinct odorants presumably results from the association of odorous ligands with specific receptors on olfactory sensory neurons. To address the problem of olfactory percep- tion at a molecular level, we have cloned and charac- terized 18 different members of an extremely large multigene family that encodes seven transmembrane domain proteins whose expression is restricted to the olfactory epithelium. The members of this novel gene family are likely to encode a diverse family of odorant receptors. Introduction In vertebrate sensory systems, peripheral neurons re- spond to environmental stimuli and transmit these signals to higher sensory centers in the brain where they are pro- cessed to allow the discrimination of complex sensory in- formation. The delineation of the peripheral mechanisms by which environmental stimuli are transduced into neural information can provide insight into the logic underlying sensory processing. Our understanding of color vision, for example, emerged only after the observation that the discrimination of hue results from the blending of informa- tion from only three classes of photoreceptors (Rushton, 1955, 1965; Wald et al., 1955; Nathans et al., 1986). The basic logic underlying olfactory sensory perception, how- ever, has remained elusive. Mammals possess an olfac- tory system of enormous discriminatory power (for reviews see Lancet, 1986; Reed, 1990). Humans, for example, are thought to be capable of distinguishing among thousands of distinct odors. The specificity of odor recognition is em- phasized by the observation that subtle alterations in the molecular structure of an odorant can lead to profound changes in perceived odor. How are the diversity and specificity of olfactory percep- tion accomplished? The detection of chemically distinct odorants presumably results from the association of odor- ous ligands with specific receptors on olfactory neurons, which reside in a specialized epithelium in the nose. Since these receptors have not been identified, it has been diffi- cult to determine how odor discrimination might be achieved. It is possible that olfaction, by analogy with color vision, involves only a few odor receptors, each capable of interaction with multiple odorant molecules. Alternatively, the sense of smell may involve a large number of distinct receptors each capable of associating with one or a small number of odorants. In either case, the brain must distin- guish which receptors or which neurons have been acti- vated to allow the discrimination between different odorant stimuli. Insight into the mechanisms underlying olfactory perception is likely to depend upon the isolation of the odorant receptors and the characterization of their diver- sity, specificity, and patterns of expression. The primary events in odor detection occur in a special- ized olfactory neuroepithelium located in the posterior re- cesses of the nasal cavity. Three cell types dominate this epithelium (Figure 1A): the olfactory sensory neuron, the sustentacular or supporting cell, and the basal cell, which is a stem cell that generates olfactory neurons throughout life (Moulton and Beidler, 1967; Graziadei and Monti Graz- iadei, 1979). The olfactory sensory neuron is bipolar; a dendritic process extends to the mucosal surface, where it gives rise to a number of specialized cilia that provide an extensive, receptive surface for the interaction of odors with the cell. The olfactory neuron also gives rise to an axon that projects to the olfactory bulb of the brain, the first relay in the olfactory system. The axons of the olfac- tory bulb neurons, in turn, project to subcortical and corti- cal regions where higher-level processing of olfactory in- formation allows the discrimination of odors by the brain. The initial events in odor discrimination are thought to involve the association of odors with specific receptors on the cilia of olfactory neurons. Selective removal of the cilia results in the loss of olfactory responses (Bronshtein and Minor, 1977). Moreover, in fish, whose olfactory system senses amino acids as odors, the specific binding of amino acids to isolated cilia has been demonstrated (Rhein and Cagan, 1980, 1983). The cilia are also the site of olfactory signal transduction. Exposure of isolated cilia from rat ol- factory epithelium to numerous odorants leads to the rapid stimulation of adenylyl cyclase and elevations in cyclic AMP (an elevation in inositol trisphosphate in response to one odorant has also been observed) (Pace et al., 1985; Sklar et al., 1986; Breer et al., 1990; Boekhoff et al., 1990). The activation of adenylyl cyclase is dependent on the presence of GTP and is therefore likely to be mediated by receptor-coupled GTP-binding proteins (G proteins) (Jones and Reed, 1989). Elevations in cyclic AMP, in turn, are thought to elicit depolarization of olfactory neurons by direct activation of a cyclic nucleotide-gated, cation-per- meable channel (Nakamura and Gold, 1987; Dhallan et al., 1990). This channel is opened upon binding of cyclic nucleotides to its cytoplasmic domain, and can therefore transduce changes in intracellular levels of cyclic AMP into alterations in the membrane potential. These observations suggest a pathway for olfactory sig- nal transduction (Figure 1 B) in which the binding of odors to specific surface receptors activates specific G proteins. The G proteins then initiate a cascade of intracellular sig- naling events leading to the generation of an action poten- tial that is propagated along the olfactory sensory axon