What Is an Odorant ? What Is a Pheromone ?

Olfaction is a critical sensory modality that allows living things to acquire chemical information from the external world. The olfactory system processes two major classes of stimuli: (a) general odorants, small molecules derived from food or the environment that signal the presence of food, fire, or predators, and (b) pheromones, molecules released from individuals of the same species that convey social or sexual cues. Chemosensory receptors are broadly classified, by the ligands that activate them, into odorant or pheromone receptors. Peripheral sensory neurons expressing either odorant or pheromone receptors send signals to separate odorand pheromone-processing centers in the brain to elicit distinct behavioral and neuroendocrinological outputs. General odorants activate receptors in a combinatorial fashion, whereas pheromones activate narrowly tuned receptors that activate sexually dimorphic neural circuits in the brain. We review recent progress on chemosensory receptor structure, function, and circuitry in vertebrates and invertebrates from the point of view of the molecular biology and physiology of these sensory systems. 307 A nn u. R ev . P hy si ol . 2 00 9. 71 :3 07 -3 32 . D ow nl oa de d fr om w w w .a nn ua lr ev ie w s. or g by G eo rg et ow n U ni ve rs ity o n 05 /0 3/ 13 . F or p er so na l u se o nl y. ANRV369-PH71-15 ARI 5 January 2009 15:25 Odorant: a volatile chemical compound, usually of molecular weight 300 or smaller, that activates olfactory neurons and induces the percept of an odor Pheromone: a substance released by a member of the same species that elicits a stereotyped behavior and/or endocrinological response in another member of the same species. Pheromones can be proteins, small molecules, or a combination thereof Conspecifics: members of the same animal species INTRODUCTION What Is an Odorant? What Is a Pheromone? An odorant is a volatile chemical compound with a molecular weight of lower than ∼300 that humans or other animals perceive as odorous via the olfactory system. The number of possible odorant molecules that exist on earth is unknown, but essentially all living things such as plants, insects, animals, and microbes emit smells—purposefully or as by-products of metabolism or waste excretion. There are also inorganic sources of odorants: Sulfur dioxide and some metals have a distinct odor. All these odorants can potentially be exploited by animals to improve their chances for survival. How many odorants are there, and how many can humans detect and distinguish? The scientific and popular literature is full of claims that the number of odorants that exist and that we can detect ranges from hundreds to thousands or even hundreds of thousands. Meanwhile, most laboratory studies in the field of olfaction use a few dozen odorants from a standard set of approximately 500 chemicals (1). The most oft-cited statistic is that humans can distinguish approximately 10,000 different odors. In his engaging book on smell (2), Avery Gilbert painstakingly traces the familiar 10,000 odors claim back through the twentieth-century scientific literature to a series of questionable assumptions in a theoretical model developed in 1927 by Ernest C. Crocker and Lloyd F. Henderson. Therefore, no one appears to have catalogued the exact number of known smells or how many such smells we can perceive. Regardless of exactly how many different odorants there may be, or how many a given animal can detect and discriminate, these small molecules are clearly important for animal survival, allowing animals to locate food and to avoid predators and environmental dangers such as fire. In contrast to general odorants, a pheromone is defined as a specific substance that is secreted by an individual and received by a second individual of the same species, or conspecific, to induce a specific reaction such as a stereotyped behavior or endocrinological change (3) [see also the book by Wyatt (4) for an excellent review on the topic of pheromones]. The term was originally coined on the basis of the identification of a volatile sex attractant, bombykol, which is released by the female silk moth Bombyx mori and elicits the full sequence of sexual behaviors in male moths (5). The definition avoids any use of the terms odor or odorant because a pheromone does not have to be odorous or volatile as long as the signal is a chemical substance that is transferred between conspecifics. Pheromones can be nonvolatile substances with a molecular weight of larger than a few hundred, including relatively large organic compounds, peptides, and proteins. In some cases, the distinctions between general odorants and pheromones are blurred. For instance, a pheromone can be an odorous compound, and an odorant can be a pheromone. As such, a pheromone released and utilized by one species can be produced as a general odorant for a second species but can be an informative odor that a third species uses to predate the second species. General odorants can also induce behavioral or physiological changes in a fashion similar to a pheromone. Insects such as moths and flies are attracted by the smell of flowers and plants, which induces stereotyped feeding behavior. We similarly experience physiological effects of general odorants elicited by trees, plants, and flowers, an effect on which the aromatherapy industry is based. These behavioral and physiological effects, however, are not categorized as pheromonal effects because the active chemical substances are not derived from conspecifics. There is an ongoing trend in the chemosensory field to extend the definition of pheromones beyond the strict definition of Karlson & Luscher (3) because there is increasing evidence that pheromones play much more diverse functional roles than are included in the above definition (4). Thus, a pheromone could be more broadly defined as a substance that is utilized for intraspecies communication even though it does not elicit obvious behavioral or endocrinological changes. We list below some 308 Touhara · Vosshall A nn u. R ev . P hy si ol . 2 00 9. 71 :3 07 -3 32 . D ow nl oa de d fr om w w w .a nn ua lr ev ie w s. or g by G eo rg et ow n U ni ve rs ity o n 05 /0 3/ 13 . F or p er so na l u se o nl y. ANRV369-PH71-15 ARI 5 January 2009 15:25 possible criteria for a more inclusive definition of a pheromone: 1. Pheromones are released by one individual and received by conspecifics; 2. pheromones themselves can send information about sex, strain, and species to the receiver; and 3. pheromonal effects must be meaningful or informative for the species. As molecular biologists, chemical ecologists, and neurobiologists continue to work together to understand the link between pheromones and behavior, the field is likely to arrive at an optimal definition of a pheromone in the future. How Are Odorants and Pheromones Detected? If one assumes that there are thousands of important odorants, how do animals recognize such a large diversity of chemical cues? Titus Lucretius Carus, a Roman poet and philosopher, proposed in 50 bce that a large variety of odors exists because each odorant possesses a unique structure (6). In the mid-twentieth century, Amoore (7) formalized this concept as the stereospecific receptor theory, which attempted to explain the molecular mechanisms underlying the remarkable olfactory sensing system. The receptor theory postulates that there are many receptor sites for odorants and that odor perception occurs only when the structure of an odorant molecule and the structure of its binding site match. Buck & Axel (8) discovered in 1991 a large multigene family encoding receptor proteins for odorants in rat; this finding was later extended to all vertebrates studied. Thus, the large number and diversity of olfactory (or odorant) receptors (ORs) confirm the essential features of Amoore’s receptor theory. Although we still cannot predict what odorants will bind to a particular OR, or how a particular odorant will smell, the stereochemical receptor theory remains the dominant theory in the field. Alternate theories proposed to explain odor perception, including vibrational, puncturing, radiational, and absorption theories, are hotly debated (9, 10) but remain unproven. OR: olfactory receptor or odorant receptor VNO: vomeronasal organ GPCR: G protein– coupled receptor Odorants and pheromones are detected by olfactory sensory neurons in the olfactory system. Mammals usually detect general odorants by the nasal olfactory epithelium via the main olfactory system. Rodents and a number of other nonprimate species possess a secondary olfactory system called the vomeronasal pathway, which detects signals via the vomeronasal organ (VNO), located at the bottom of the nasal cavity. The appearance of the VNO coincided with the acquisition of the lung respiratory system during the Cambrian explosion (11), and the VNO became genetically vestigial during the evolution of the primate lineage (12). Similarly, most insects also have two olfactory organs, the antenna and the maxillary palp, although insects differ in the extent to which each organ is dedicated to general odorants, pheromones, or even nonolfactory cues such as taste and mechanical stimuli. Recent evidence suggests that the labial palps, typically thought to be exclusively taste organs, can also sense odors (13). In this review, we summarize the current knowledge of chemosensory receptors for odorants and pheromones, point out what is common and what is different in chemosensing mechanisms between invertebrate and vertebrate animals, and discuss how sexually dimorphic responses to chemosignals are encoded in the brain. CHEMOSENSORY RECEPTOR GENES Vertebrate Olfactory Receptors The vertebrate OR genes encode a large family of seven-transmembrane-domain G protein– coupled receptors (GPCRs) that play a role in recognizing odorant molecules in the olfactory epithelium (14). OR proteins were classified as members of t