The nosey business of olfaction

Compared to other senses, the sense of smell is often underappreciated. Olfactory Receptors (ORs) are proteins that bind to odorant molecules and are responsible for our sense of smell or olfaction. Sensing the chemical environment is vital for the continued existence of all organisms. A well developed olfactory system with appropriate selectivity and sensitivity is therefore essential to properly interpret and react to the environment. These ORs are thus equipped for sensing the chemical stimuli from our environment enabling suitable responses critical to health, survival, social interactions and reproduction. Animals including humans can not only smell many different compounds in their environment but also distinguish between them. This requires that the different odorant molecules stimulate different receptors.

The odorant receptor gene family consisting of about 1000 genes constitutes the largest known multi-gene family in the human genome. However, only 350 of these encode potentially functional and working ORs while a substantial fraction are non-functional pseudogenes arising possibly due to gene duplication (1). A comparison between humans and other mammalian OR repertoires shows that humans may have much-reduced sensitivity to certain odors compared to chimps, dogs and mice, suggesting a deterioration of OR system occurred during evolution. Another interesting feature is that OR genes are typical found in gene clusters on almost all chromosomes, except chromosome 20 and Y. Linda Buck and Richard Axel won the Nobel Prize in 2004 for their work on cloning and characterizing the OR gene family, establishing the molecular basis for odor recognition (2).

This ‘family’ of ORs constitute a highly diverse set of functions ranging from enzymes to ligand-gated ion channels as well as G protein-coupled receptors (GPCRs) involved in primary detection of olfactory stimuli. A single type of olfactory receptor is present on each olfactory receptor cell (ORCs). However, each receptor can be activated by different odor molecules and each odor molecule can activate different ORs on different cells increasing their diversity. Thus, the various chemical compounds (both natural and artificial) that stimulate the different ORCs and the interaction between them allows us to detect a variety of smells. Millions of such ORCs having different ORs capable of sensing different chemical stimuli are present within the nasal cavity forming the olfactory epithelium. These ORCs have long slender extensions called cilia that are covered by mucous for detection and response to odor molecules by ORs.  Sensory neurons lining the nasal epithelium then convey the signal from different odors via electrical impulses to the brain that recognizes and makes the memory connections; which is why certain smells can bring up particular memories. The reduced repertoire of ORs in humans is compensated by the greater processing capacity of the human brain (3). However, how the olfactory information is interpreted and processed by the brain is still not fully understood. Recent studies suggest that our sense of smell actually outperforms other senses such as sight and hearing. Scientists predict that humans are actually capable of detecting trillions of different smells. Additionally, our sense of smell is closely connected to our sense of taste, which explains why food tastes bland when we have a bad cold. 🙂

From the proteomics viewpoint, ORs have gained a dubious reputation. They are particularly difficult to detect due to their transmembrane architecture, low transcript expression and possible tissue specificity, being confined to nasal tissues. Although ORs have little role outside of the olfactory system, there are isolated reports of odorant receptors in the kidney (4) and testes (5) where they are said to play a role in sensing gut microbiota and sperm chemotaxis respectively. Interestingly, despite lack of nasal tissues in the large scale proteomic analyses conducted by teams led by Akhilesh Pandey and Bernard Kruster (that led to the first drafts of the human proteome), both carried evidence for the presence of 108 ORs and 200 ORs respectively (6). Most of them turned out to be wrong calls owing to the low spectral quality or non-discriminatory shared peptides. This study exposed the difficulties inherent in identifying ORs by current proteomic technologies.

In conclusion, the study of the complexity of the human olfactory system is important not only to understand human evolution but also changes in human behavior and diet over the ages that is deeply tied to human memory and emotion and how we can use this information to interact successfully with the changing environment as our perception grows.

References:

1. Malnic, B., Godfrey, P. A., and Buck, L. B. (2004) The human olfactory receptor gene family, Proc Natl Acad Sci U S A 101, 2584-2589.
2. Antunes, G., and Simoes de Souza, F. M. (2016) Olfactory receptor signaling, Methods Cell Biol 132, 127-145.
3. Sarafoleanu, C., Mella, C., Georgescu, M., and Perederco, C. (2009) The importance of the olfactory sense in human behavior and evolution, J Med Life 2, 196-198.
4. Natarajan, N., and Pluznick, J. L. (2016) Olfaction in the kidney: ‘smelling’ gut microbial metabolites, Exp Physiol 101, 478-481.
5. Vosshall, L. B. (2004) Olfaction: attracting both sperm and the nose, Curr Biol 14, R918-920.
6. Ezkurdia, I., Vazquez, J., Valencia, A., and Tress, M. (2014) Analyzing the first drafts of the human proteome, J Proteome Res 13, 3854-3855.