Combinatorial receptor codes for odors.

Abstract

sweaty (Arctander, 1969). Curiously, the perceived qual-Bettina Malnic,* Junzo Hirono, † Takaaki Sato, † ‡ ity of an odorant can also differ with a change in its and Linda B. Buck* ‡ concentration. Indole, for example, has a putrid odor * Howard Hughes Medical Institute when concentrated but is perceived as floral when di-Department of Neurobiology luted. Sensitivity to odorants also varies, with some Harvard Medical School odorants detectable at a much lower concentration than Boston, Massachusetts 02115 others (Cain, 1988). In addition, there are individual dif-† Life Electronics Research Center ferences in olfactory perception. Androstenone, a pig Electrotechnical Laboratory pheromone, is a striking example; at a low concentra-Amagasaki 661 tion, androstenone has a mild, pleasant odor to some, a Japan disgusting urinous odor to others, and still others cannot smell it at all (Amoore, 1970). Neither the mechanisms by which the olfactory sys-Summary tem accomplishes its perceptual feat nor the bases of these perplexing features of olfactory perception are The discriminatory capacity of the mammalian olfac-well understood. Studies of rodent olfactory systems tory system is such that thousands of volatile chemi-have, however, provided information about the structure cals are perceived as having distinct odors. Here we and cellular functioning of the mammalian olfactory sys-used a combination of calcium imaging and single-tem, as well as molecular tools that now permit queries cell RT-PCR to identify odorant receptors (ORs) for into the molecular bases of olfactory perception. Volatile odorants with related structures but varied odors. We odorants that enter the nose are detected by millions found that one OR recognizes multiple odorants and of olfactory sensory neurons (olfactory neurons) (Shep-that one odorant is recognized by multiple ORs, but herd, 1988; Buck, 1996). These neurons transmit signals that different odorants are recognized by different to the olfactory bulb of the brain, which, in turn, sends combinations of ORs. Thus, the olfactory system uses signals to the primary olfactory cortex. From there, olfac-a combinatorial receptor coding scheme to encode tory information is relayed both to higher cortical areas odor identities. Our studies also indicate that slight and to the limbic system, thereby allowing for both the alterations in an odorant, or a change in its concentra-conscious perception of odors and their emotional and tion, can change its "code," potentially explaining how motivational effects. such changes can alter perceived odor quality. The detection of odorants is mediated by 1000 different G protein-coupled odorant receptors (ORs) that are encoded by a multigene family (Buck and Axel, 1991; Levy et al., 1991; Lancet and Ben-Arie, 1993; Ngai et al., Introduction 1993). ORs share characteristic sequence motifs, but they vary in sequence, consistent with an ability to rec-The mammalian olfactory system possesses enormous ognize diverse ligands. Several findings indicate that discriminatory power. Humans are thought to have a each olfactory neuron expresses only one OR gene. poor sense of smell compared to other animals, and yet First, individual OR gene probes hybridize to only 0.1% they can perceive a vast number of volatile chemicals. of olfactory neurons in situ (Nef et al., 1992; Strotmann Odorants, typically small organic molecules of less than et al., 1992; Ressler et al., 1993; Vassar et al., 1993). 400 Da, can vary in a number of parameters, including Second, by reverse transcriptase-polymerase chain re-size, shape, functional groups, and charge (Amoore, action (RT-PCR) analysis of small numbers of olfactory 1970). They include a panoply of diverse aliphatic acids, neurons, a single neuron expresses only one allele of a alcohols, aldehydes, ketones, and esters; chemicals given OR gene (Chess et al., 1994). Finally, using single-with aromatic, alicyclic, polycyclic, and heterocyclic ring cell RT-PCR, only one OR species can be identified structures; and innumerable substituted chemicals of per olfactory neuron (C. Dulac and R. Axel, personal each of these types, as well as combinations of them. communication). Remarkably, these molecules are not only detected by In the nose, neurons expressing a given OR are con-the olfactory system, but also discriminated by it. fined to one of four OR expression zones, where they Human studies have provided information about ol-are randomly interspersed with neurons expressing factory perception that is both surprising and puzzling. other ORs (Ressler et al., 1993; Vassar et al., 1993; Strot-They have demonstrated that even a slight change in mann et al., 1994). In the olfactory bulb, the axons of the structure of an odorant can cause a dramatic shift neurons expressing the same OR converge at fixed sites in its perceived odor (Beets, 1970; Polak, 1973). For in only a few of the bulb's 2000 glomeruli (Ressler et example, when the hydroxyl group of octanol is replaced al., 1994; Vassar et al., 1994; Mombaerts et al., 1996). by a carboxyl group to give octanoic acid, its perceived This suggests that olfactory information is first roughly odor changes from orange and rose-like to rancid and organized into four large sets in the nose and then reorganized in the olfactory bulb into a sensory map, which is identical in different individuals. In both the nose and ‡ To whom correspondence should be addressed (e-mail: lbuck@ hms.harvard.edu [L. B. B.], tasato@etl.go.jp [T. S.]). bulb, information derived from different ORs is strictly