Among the five senses, humanity's understanding is biased toward sight, hearing and touch. The more complex, integrated senses of taste and smell have only become popular fields of inquiry in the last two decades. Smell, or olfaction, is for humans by definition the sense which detects and identifies the presence of chemicals in the surrounding air. Other higher vertebrates have a much more finely developed olfactory sense while lesser vertebrates and invertebrates use other sensors on their bodies to detect chemicals in the air immediately surrounding them. Smell can help one form an opinion on the chemical in question without contact and can continue to influence the perception of the chemical during contact, while contact can reveal different details about the chemical. Despite the somewhat devolved sense of smell in humans, in most mammals the sense of smell is nearly as important as vision.
Air-breathing vertebrates have large cavities in the front of their skulls known as sinuses. Generally accessible through the nose and the throat, the epithelial lining of the sinuses is packed with nerves sensitive to different chemicals. These olfactory receptor patches are located high in the inner nose, one on each side, and in mammals are composed of a 2.5 cm2 yellow-colored membrane. Olfactory sensory neurons (OSNs) connect the olfactory receptor patches to the two olfactory bulbs of the brain, which are located on either side of the upper inner nose. Each olfactory receptor neuron has between six and twelve cilia on the end where the olfactory receptor proteins are located. For the purposes of this paper, a receptor is defined as the transmembrane protein located on the cilia of the OSNs. In order for chemical scent identification to occur, the chemical needs to first dissolve in the mucous lining of the sinuses. Once the chemical has come in contact with the mucous lining and dissolved in it, the odorant ligand binds to the olfactory receptors on the cilia of the OSNs. It is this binding which triggers an action potential in the OSNs and begins the process of scent identification. In total, there are about 10 million OSNs in humans which have terminations in the olfactory receptor patches. (Dennis, 2004)
Even though there are a number of different olfactory receptors in any given organism with the capacity to smell, biochemical evidence has shown they are all G protein-coupled receptors composed of proteins with seven membrane-spanning domains. (Mombaerts, 1999) The particular seven-transmembrane proteins which serve as olfactory receptors share common amino acid sequences which distinguish them from other seven transmembrane proteins. Leu-His-Thr-Pro-Met-Tyr is in the first intracellular loop of the transmembrane protein. Met-Ala-Tyr-Asp-Arg-Tyr-Val-Ala-Ile-Cys is found at the end of the third transmembrane domain and at the beginning of the second intracellular loop. The end of transmembrane domain five contains Ser-Tyr, the sixth transmembrane domain starts with Ser-Thr-Cys-Ser-Ser-His, and the seventh transmembrane domain contains Pro-Met-Leu-Asn-Pro-Phe. Differences between the various olfactory receptors are found in the amino acid sequences of the third, fourth and fifth transmembrane domains. It is these seemly small differences between the proteins which account for the one thousand or more different olfactory receptor genes found in various species.
The genes which code for olfactory receptors are members of the largest family of genes in vertebrates. (Zhang and Firestein, 2002) The recent completion of the mouse and human genome projects has made it possible to determine how many genes might code for different types of olfactory receptors. Using the mouse genome decoded and released by Celera in May of 2000, Zhang and Firestein were able to calculate that there are 1,296 genes in mice which code for olfactory receptors. First, sequences which are known to code for olfactory receptors in mice and humans were identified in the Celera Assembled and Annotated Mouse Genome using Celera’s search service, giving a result of 1,405 possible olfactory receptor genes. These results were narrowed down by confirming the potential olfactory receptors had characteristics deemed required for olfactory receptor genes, such as seven transmembrane domains and expected lengths for the N and C terminal ends of the gene, and 759 of the original 1,405 gene sequences met the qualifications. The eliminated sequences were then subjected to further analysis and comparison to known olfactory receptor gene sequences from both humans and mice, as the lengths of the N and C terminals may vary, yet still code for a functioning olfactory gene. A final number of 1,296 olfactory genes was arrived at after the final analysis. In mice, ~20% of these olfactory genes appear to be pseudogenes, which are genes which due to the deletion of large portions of the gene no longer code for anything that could possibly be functional yet likely were functional before the mutation occurred. After the release of the human genome, a similar analysis was performed and about 900 potential olfactory receptor genes were identified and ~60% of these appeared to be pseudogenes. These genes and pseudogenes can be found on all chromosomes except chromosome 20 and the Y chromosome in humans, which is atypical as families of genes tend to be on the same chromosome.
The difference in percentage of olfactory receptor pseudogenes may seem somewhat peculiar, but when the numbers of pseudogenes are viewed in light of the dependency of the mouse on smell versus that of a modern human, these numbers make more sense as smell could be considered a mouse's primary sense. Humans have a more highly developed sense of vision and tend to use visual identification as opposed to scent identification of objects and beings. By selecting 100 olfactory receptor genes at random in 19 different species and comparing the percentage of suspected pseudogenes to the level of development of full color vision in the animal in question, Gilad et. al. (2004) were able to show that the increase in the number of pseudogenes in primates such as humans correlates with the development of full color vision in the primate in question, though direct causation has not been and would be difficult to confirm. The need for such a wide repertoire of olfactory perception decreased as higher primates relied more heavily on their vision for survival purposes. It is likely that the differences in what people claim to be able to smell result from having different olfactory genes being inactive in their genome.
Each olfactory sensory neuron’s group of cilia has only one type of olfactory receptor. (Serizawa et. al., 2003) This leads to the one receptor-one neuron rule, though the mechanism which ensures that only one gene is turned on at a time still remains a mystery. According to Serizawa et. al. (2003), the existence of only one type of receptor on a neuron is required for accurate signal interpretation in the olfactory bulb though that team did not give any details on why this must be the case.
Since ~60% of the olfactory receptor encoding genes in humans are actually pseudogenes that code for non-functional receptors, one would think a similar percentage of the actual receptors in humans are incapable of detecting a possible smell. This is not actually the case. Serizawa et. al. (2003) cloned mice containing a customized version of olfactory gene MOR28, which they had modified to contain a sequence coding for a fluorescent protein and removed the coding region of the gene so it would produce a non-functioning receptor. Using a fluorescent microscope they were able to find that the pseudogene was expressed in the olfactory receptors of the cloned mouse. Using an RNA probe which was designed to only recognize the coding portion of the same olfactory receptor gene’s DNA, the team found that in receptors with the inactive copy of MOR28 a second, functional of MOR28 was expressed. These results imply that when a pseudogene is selected for expression in an olfactory receptor, while it is still expressed, a second, functioning gene is also expressed, with the result that all olfactory receptors are functional.
Located in the olfactory bulb are thousands of processing modules known as "glomeruli" which are distinct, spherical clumps of olfactory sensory neuron dendrites. (Mori et. al., 1999) In mice, these glomeruli are located in four different zones of the olfactory bulb. The neurons which terminate in each zone originate in the corresponding zone of the olfactory receptor patch and each glomerulus is the termination point of several thousand neurons. Within each zone, the different types of OSNs are fairly evenly distributed, with OSNs which express receptors with similar amino acid sequences being in the same zone of the olfactory epithelium. While the hypothesis that each glomerulus only takes input from one type of olfactory receptor neuron has been investigated and seems likely, it has not been confirmed.
The olfactory bulb is responsible for transforming the olfactory receptor neuron’s signal into information the olfactory cortex can process. Since most if not all of the olfactory neurons stemming from one type of receptor end in one glomerulus, and postsynaptic neurons extending from the olfactory bulb to the olfactory cortex only originate from one glomerulus, it seems a safe assumption that any change in the signal must occur within the olfactory bulb. Using Drosophila, whose olfactory cortices only contain 40 glomeruli, the action potentials of postsynaptic neurons and OSNs can be recorded and their responses to various stimuli explored. (Wilson et. al., 2004). This is possible in Drosophila because they have a small enough number of glomeruli to be tracked using patch clamps to monitor the current passing through a neuron at various points in time.
In tests done with smells that result from one type of molecule, such as benzaldehyde or 3-octanol, it was shown the that responses in the olfactory cortex to a stimulus were far more complex than those in the olfactory bulb and that signals from other olfactory sensory neurons likely change an OSN’s signal within the olfactory bulb. (Wilson et. al., 2004) Additionally, postsynaptic neurons which originated from the same glomerulus showed similar action potential responsive patterns to the same odor, while the responsive patterns of postsynaptic neurons on other glomeruli could be wildly different. There was also no constant trend for the action potential response patterns of postsynaptic neurons as some neurons experienced an action potential regardless of the chemical, some only experienced action potentials when exposed to select chemicals, and some (about one-fifth) never experienced an action potential as a result of any chemical tested. The majority of OSNs and postsynaptic neurons seemed to experience an action potential to any kind of chemical stimulus. Even if the originating olfactory neuron for a postsynaptic neuron only showed a weak response, the postsynaptic neuron could still have a strong response. To explain this behavior, it has been hypothesized that despite originating at only one glomerulus, postsynaptic neurons integrate signals from a number of different types of olfactory receptor neurons via interactions between the glomeruli within the olfactory bulb.
Despite the recent surge in research, olfaction is still poorly understood. To date, how the olfactory receptors distinguish between different chemicals has not been discovered. Additionally, while the processing of olfactory signals in the mammalian olfactory cortex is assumed to be similar to that of an insect such as Drosophila, it is still unclear whether or not insect olfactory processing is an adequate model for that of higher vertebrates. The human response to scent is very complex and can be very powerful, even to the point of invoking a physical response. It is the method of identification that the olfactory cortex uses to match a response to a sensed chemical which presents one of the field’s greatest challenges. Now that the groundwork has been laid, it is finally possible to tackle this sort of complex question about olfaction. With luck, the next decade will bring the same sorts of insights into smell that are already taken for granted with vision and hearing.
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