"That which we call a rose by any other name would smell as sweet": How the Nose knows!

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Terence Kennedy
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understanding of how odors are perceived.

(left) Sayanti Saha is a PhD student in the Department of Molecular Reproduction, Development and Genetics, lise. She is working in the broad area of cellular signal transduction.

1 "That which we call a rose by any other name would smell as sweet": How the Nose knows! Nobel Prize in Physiology or Medicine 2004 Sayanti Saha, Parvathy Ramakrishnan and Sandhya S Vis'Wes'Wariah Richard Axel and Linda B Buck received the Nobel Prize for their discoveries leading to an understanding of how odors are perceived. A large family of receptors present in the nasal epithelium are activated by specific odorants and relay information on the signal to the brain, allowing us to have the sense of smell. (left) Sayanti Saha is a PhD student in the Department of Molecular Reproduction, Development and Genetics, lise. She is working in the broad area of cellular signal transduction. (right) Parvathy Ramakrishnan is a final year BTech. Biotechnology student in Anna University, Chennai. (center) Sandhya S Visweswariah is an Associate Professor in the Department of Molecular Reproduction, Development and Genetics, lise. Her laboratory is interested in cyclic nucleotide signaling mechanisms in both prokaryotes and eukaryotes. The 'sweet smell of success' greeted Richard Axel and Linda B. Buck as the two US neuroscientists were awarded the 2004 Nobel Prize in Physiology or Medicine for their discoveries of "odorant receptors and the organization of the olfactory epithelium". Their research provided the first key insights about the complex network that governs our sense of smell. Their discovery of the family of olfactory receptor proteins and how they work in a combinatorial fashion to relay signals to the brain led to the understanding of how mammals can discriminate between an infinite number of odors and how odors are perceived by the brain. In all organisms, survival depends on elaborate intracellular and intercellular communication networks. In the case of sensory signaling, the environmental stimuli are interpreted as the first step in sensory perception. Olfaction is an ancient sense. Its precursors can be found in the most primitive single-celled organisms reflecting the need of every organism to sense its chemical milieu. In mammals, the olfactory system can detect and distinguish a vast number of volatile chemicals with a large variety of structures. Olfactory perception requires recognition of the diverse repertoire of odorous molecules in the periphery ~ R-E-S-O-N-A-N-C-E-I--M-a-rc-h

GENERAL I ARTICLE ---""""-Olfactory cilia Supporting/ sustentacular cell Olfactory sensory neuron I lij-~--* Dendrite Olfactory sensory neuron Glomeruli To olfactory bulb as well as the more central

Olfactory bulb. The primary events in odor detection occur in a specialized olfactory neuroepithelium (a pseudo-stratified columnar epithelium), which in mammals, lines the posterior nasal cavity.

Olfactory neurons are shortlived cells that generally live for only 30-60 days and are continuously replaced from the basal layer of olfactory stem cells.

2 GENERAL I ARTICLE ---""""-Olfactory cilia Supporting/ sustentacular cell Olfactory sensory neuron I lij-~--* Dendrite Olfactory sensory neuron Glomeruli To olfactory bulb as well as the more central mechanisms that allow the discrimination of odors. Cellular Composition of the Olfactory Neuroepithelium and Olfactory Bulb Figure 1a (left). Olfactory neuroepithelium. Figure 1 b (right). Olfactory bulb. The primary events in odor detection occur in a specialized olfactory neuroepithelium (a pseudo-stratified columnar epithelium), which in mammals, lines the posterior nasal cavity. There are three principal cell types in the olfactory epithelium: olfactory sensory neurons, supporting cells (sustentacular cells) and olfactory stem cells (Figure la). Olfactory neurons are shortlived cells that generally live for only days and are continuously replaced from the basal layer of olfactory stem cells. The olfactory sensory neuron is bipolar; a dendritic process extends from its apical surface 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. From its opposite pole, each olfactory neuron projects a single unbranched axon. The axons of the olfactory neuron synapse with dendrites from cells in the olfactory bulb, the first relay station for olfactory signaling in the brain. The cells in the Keywords Odorant, receptor, G-protein coupled receptors, signal transduction. -R-ES-O--N-A-N-C-E-I--M-a-rc-h ~~~

3 Olfactory sensory neurons are the only neurons in the nervous system exposed to the external environment and harbor the receptors that detect various odorants. Odorous ligands: Molecules that bind to specific odorant receptors, and activate the receptors so that their 'smell' is perceived. olfactory bulb in tum project axons to higher cortical centers via the olfactory tract (Figure 1 b). The Discovery of Olfactory Receptors and Coding of Information in the Olfactory System Linda Buck first got excited about neurosciences as a senior post-doctoral student in Axel's lab. Their co-publication of that work in 1991 is considered a landmark in the study of the nervous system. The paper published in the journal Cell described odorant receptors for the first time. Olfactory sensory neurons are the only neurons in the nervous system exposed to the external environment and harbor the receptors that detect various odorants. The paper described a family of about 1000 genes (nearly 3% of the total number of genes in mammals), which encode olfactory receptors in mice. The olfactory multigene family encodes a series of proteins that are members of a large superfamily of G-protein coupled receptors (GPCRs). Comparison of the protein sequences of a number of olfactory family GPCRs showed that these proteins share sequen~e motifs that are not present in other members of the superfamily. They also display considerable diversity among themselves, the extent and patterning of which is consistent with an ability of this large family to bind to a variety of structurally diverse odorous ligands l. After the first breakthrough paper, both worked independently to answer fundamental questions about how the brain notices odors wafting through the air. Both are now investigators at the Howard Hughes Medical Institute, with Richard Axel working at Columbia University and Linda Buck at the Fred Hutchinson Cancer Research Center, University of Washington in Seattle. In order to discriminate among odorants, the brain has to know which of the numerous olfactory receptors have been activated. To understand the organizational strategies underlying this discriminatory capacity of mammals, Buck examined the spatial distribution of odorant receptor mrnas in the mouse olfactory ~ R-ES-O-N-A-N--CE--I-M-a-r-ch

4 GENERAL I ARTICLE epithelium and demonstrated that there is a topographical patterning of odorant receptor gene expression in the olfactory epithelium. There are four distinct spatial zones where different sets of olfactory receptor genes are expressed. The expression zones exhibit bilateral symmetry in the two nasal cavities and are virtually identical in different individuals. In mammals, neurons expressing a given olfactory receptor are confined to one of the four olfactory receptor expression zones, where they are randomly interspersed with neurons expressing other olfactory receptors. It is also suggested that each olfactory sensory neuron expresses only one olfactory receptor gene, thus hinting towards a functionally distinct nature of the individual olfactory neurons. Thus, the activation of a particular olfacrory receptor can be understood as the activation of a particular olfactory neuron. In mammals, neurons expressing a given olfactory receptor are confined to one of the four olfactory receptor expression zones, where they are randomly interspersed with neurons expressing other olfactory receptors. Axel and Buck independently set forward to answer whether neurons expressing a given receptor project their axons to common glomeruli within the olfactory bulb. They demonstrated that the neurons expressing a given receptor project to one or a few glomerular targets among the thousands of glomeruli within the olfactory bulb. Moreover, the position of specific glomeruli is bilaterally symmetric and is constant in different individuals within a species. Thus, exposure to a given odorant stimulates a spatially restricted set of glomeruli within the olfactory bulb of the brain. This suggests that olfactory information is first roughly 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. During her studies to link odorant receptors with specific odorants, Buck found that one olfactory receptor recognizes multiple odorants and one odorant is recognized by multiple olfactory receptors. In addition, different odorants are recognized by different combinations of olfactory receptors. Thus, the mammalian olfactory system uses a combinatorial receptor coding scheme to encode odor identities (Figure 2). Slight alterations in -R-ES-O-N-A-N--C-E-I-M--ar-c-h ~ ~

Figure 2. Schematic representation showing combinatorial receptor codes for odorants. Receptors activated with odorants are shown with a halo of orange around them.

Odorants, Odorant Receptors and Sensory Transduction in the Olfactory Epithelium 2 G-protein coupled receptors: These are receptors in cells that interact with proteins which in turn are regulated by

5 Figure 2. Schematic representation showing combinatorial receptor codes for odorants. Receptors activated with odorants are shown with a halo of orange around them. Odorants Odorant Receptors the structure of an odorant, or a change in odorant concentration, can change its receptor code. Odorants, Odorant Receptors and Sensory Transduction in the Olfactory Epithelium 2 G-protein coupled receptors: These are receptors in cells that interact with proteins which in turn are regulated by the binding of GTP/GDP. (Hence the name of 'G-protein'). The receptors have 7 stretches of hydrophobic amino acids in their polypeptide chain, which allow the receptor protein to stay anchored in the cell membrane. Mammals possess an olfactory system of enormous discriminatory power. The detection of chemically distinct odorants results from the association of odorous ligands (odorants) with olfactory receptors on the cilia of olfactory sensory neurons. Odorants are small, usually lipophilic molecules that traverse the aqueous nasal mucus by binding to soluble odorant-binding proteins (OBPs). Olfactory receptors are members of the G-protein 2 coupled receptors, which are seven-transmembrane spanning domain receptors. The transmembrane domains show exceptional di versity among olfactory receptors and thus are proposed to be directly involved in ligand binding. The binding of odorants to olfactory receptors activates a G-protein (G~Olf)' which stimulates adenylyl cyclase type III (AC) causing an increase in camp. The camp opens a cyclic nucleotide-gated (CNG) cation channel, resulting in an influx ofna+ and Ca+ 2 This leads to a change in ~~ R-E-S-O-N-A-N-C-E-I--M-a-rc-h S

$GENERAL I ARTICLE Initiation of olfactory signal ~ ~ \ f» "" Figure 3. Olfactory signal transduction.$ Signal termination may occur from the phosphorylation of odorant receptors by protein kinases such as camp-activated protein kinase CPKA).

Signal termination may occur from the phosphorylation of odorant receptors by protein kinases such as camp-activated protein kinase CPKA).

(Figure 3) The olfactory system is also responsible for the sensing of pheromones in lower vertebrates and insects.

Sensory neurons in the VNO are connected to the accessory olfactory bulb as opposed to the olfactory neurons from the olfactory epithelium, which are connected to the main olfactory

6 GENERAL I ARTICLE Initiation of olfactory signal ~ ~ \ f» "" Figure 3. Olfactory signal transduction. Olfactory receptor (seven- ransmembrane) Termination of olfactory signal membrane potential that culminates in action potential generation in the olfactory axon. Signal termination may occur from the phosphorylation of odorant receptors by protein kinases such as camp-activated protein kinase CPKA). Ca+ 2 flux through the cyclic nucleotide-gated channel may also lead to channel closure mediated by a Ca+ 2 binding protein (CBP). (Figure 3) The olfactory system is also responsible for the sensing of pheromones in lower vertebrates and insects. In these animals it meets the dual requirements of general odor sensing and pheromone sensing by harboring a second olfactory sense organ, called the vomeronasal organ (VNO). Sensory neurons in the VNO are connected to the accessory olfactory bulb as opposed to the olfactory neurons from the olfactory epithelium, which are connected to the main olfactory bulb. From the accessory olfactory bulb, signals are transmitted to the areas of the amygdala and hypothalamus, which have been involved in certain pheromone effects. Subsequent research has revealed that humans have fewer working olfactory receptor genes than rodents - only The olfactory system is also responsible for the sensing of pheromones in lower vertebrates and insects. -RE-S-O-N-A-N-C-E--I-M-a-r-Ch~ ~ ~-

about 350 - and they have also lost the VNO organ during evolution.

Thus, one can consider that the sense of smell is more developed in the rodents and other nonhuman vertebrates. Richard Axel LindaB Buck Recipients of Nobel Prize.

7 about and they have also lost the VNO organ during evolution. We are all aware that dogs have a keener sense of s~ell than humans and dogs have nearly 40 times more area of olfactory epithelium than humans! Thus, one can consider that the sense of smell is more developed in the rodents and other nonhuman vertebrates. Richard Axel LindaB Buck Recipients of Nobel Prize. Medical Importance of the Study Although their work is not directly related to any major human disease, the studies of Axel and Buck have revealed how the complex patterns of connections are formed in the brain. Since the olfactory receptors are members of the GPCRs and the latter are often disrupted in cancer and other diseases, understanding how this large family of receptors works is of importance to biomedical research. Understanding of odor perception can also provide relief to patients undergoing chemotherapy whose sense of smell is impaired by the potent drugs. Though Axel's and Buck's work has answered important questions about the sense of smell, it has also posed additional questions such as how an olfactory neuron chooses which receptor gene to express. According to Buck, "The olfactory system is a wonderful, never-ending puzzle". Suggested Reading Address for Correspondence Sandhya S Visweswariah Department of Molecular Reproduction. Development and Genetics Indian Institute of Science Bangalore India. sandhya@mrdg.iisc.ernet.in [1] [2] L Buck and R Axel, A novel multigene family may encode odorant receptors: a molecular basis for odor recognition, Cell, Vol. 65, pp , [3] KJ Ressler, S L Sullivan and L B Buck, A zonal organization of odorant receptor gene expression in the olfactory epithelium, Cell, Vol. 73, pp , [4] R Vassar, S K Chao, R Sitcheran, J M Nunez, L B Vosshall and R Axel, Topographic organization of sensory projections to the olfactory bulb, Cell, Vol. 79, pp , [5] B Malnic, J Bimno, T Sato, and L B Buck, Combinatorial receptor codes for odors, Cell:t Vo1.96, pp ,1999. [6] L B Buck, The molecular architecture of odor and pheromone sensing in mammals, Cell, Vol.lOO, pp , ~ R-ES-O--N-A-N-C-E-I--M-a-rc-h

Lecture 9 Olfaction (Chemical senses 2)

Lecture 9 Olfaction (Chemical senses 2) All lecture material from the following links unless otherwise mentioned: 1. http://wws.weizmann.ac.il/neurobiology/labs/ulanovsky/sites/neurobiology.labs.ulanovsky/files/uploads/kandel_ch32_smell_taste.pd