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Making Scents of the World: Nobel Prize-Winning Research

David Micklos
DNA Learning Center, Cold Spring Harbor Laboratory

My terrier, Harley, spends most of his life with his nose to the ground. The intensity of his olfactory surveillance makes me think that the world must smell entirely different to him than it does to me. Recent research on the molecular genetics of sensory receptors gives us a clue to Harley and other animals' preoccupation with smell—and why the world, indeed, does smell different to different creatures.


Where smell and taste begin

At the molecular level, smell and taste perception are good examples of signal transduction, where a biological message is (trans)mitted across a biological membrane. It also refers to the physical and biochemical changes that occur as the signal is (trans)ferred between a series of molecules to affect a change within a cell. The sense of smell or taste begins when a molecule (a ligand) binds to a specific receptor on the surface of specialized cells in the epithelial layer of the nasal cavities or tongue. The binding of the ligand induces structural changes in the receptor molecule, which conducts the signal through the cell membrane into the interior of the cell. Just inside the cell membrane, taste and smell receptors bind to a class of intracellular messengers, the G-proteins. This name refers to the molecule's activation by the exchange of the guanosine nucleotide GTP for GDP. Once activated, the G-protein transduces the signal on to other molecules inside the cell. The (trans)mission of the signal is often accomplished by the addition or removal of phosphate groups, which activates the next molecule in the pathway.


The role of GPCRs

G-protein coupled receptors (GPCRs) are also known as seven-(trans)membrane receptors. In between the external ligand-binding and internal G-protein binding domains, the protein loops 7 times through the cell membrane. Four Nobel prizes have been awarded for work on GPCRs. Robert Lefkowitz and Brian Kobilka shared the 2012 Nobel Prize in Chemistry for working out the structural and biochemical basis of G-protein signal (trans)duction. Richard Axel and Linda Buck shared the 2004 Nobel Prize in Physiology or Medicine for working out the "olfactory code," showing the combinatorial effect of the ligand binding that allows the brain to recognize an array of odors. Different GPCRs can bind the same odorant molecule, and different odorant molecules can bind to different parts of the same GPCR—making for almost endless combinations that can specify different kinds of smells.

With at least 800 members, the GPCRs are the largest gene family in the human genome. GPCRs are involved in a number of types of signaling and are the targets of about 30% of all drugs. In addition to the olfactory and taste receptors, this super-family includes receptors for the neuro(trans)mitters glutamate, dopamine, and serotonin, for hormones and pheromones, and for histamines. The GPCR rhodopsin in the retina of the human eye is closely related to bacterial rhodopsin, providing evidence for the antiquity of GPCRs as environmental sensors.

The large size of this GPCR gene family is related to the very small size of the genes that encode GPCRs. Like bacterial genes, each GPCR is a single open reading frame (ORF) of about 1,000 nucleotides—or some would say a single exon—without any introns. Their small size makes them easy to duplicate, and certain regions of mammalian chromosomes—such as the short arm of human chromosome 11—are clusters of duplicated olfactory and taste receptors.


Still evolving

The sensory receptors are among the most rapidly evolving genes in the human genome. Point mutations, or single nucleotide polymorphisms (SNPs), may change key amino acids in the extracellular domain, allowing receptors to evolve that bind different ligands and differentiate the olfactory and taste "codes." Carolina's Using a Single Nucleotide Polymorphism (SNP) to Predict Bitter Tasting Ability kits enable students to correlate a SNP in the bitter taste receptor (TAS2R38) to their ability to taste the bitter substance phenylthiocarbamide (PTC). Students with 1 variation of the SNP tend to be tasters, while students with an alternative variation tend to be non-tasters. Interestingly, this mutation is not located in the external or internal binding domains of the receptor protein. Rather, it is found in 1 of the transmembrane regions, suggesting that it interferes with the conformational (structural) changes needed to transduce the bitter taste signal through the cell membrane. For more detailed information about this experiment, see my previous Carolina Tips® article, "Coming into the Genome Age III: The Molecular Genetic Basis of PTC Tasting." For more details and experiments on the human genome, also see my new book, Genome Science: A Conceptual and Practical Introduction to Molecular Genetic Analysis in Eukaryotes.

A point mutation also can introduce premature stop codon, rendering a sensory receptor a "pseudogene" that produces a truncated, nonfunctional protein. If there is no evolutionary pressure to maintain a particular sensory receptor, over time the pseudogene becomes "fixed" in the human population, meaning that all humans have 2 copies of the nonfunctional gene. About 2/3 of human olfactory receptors are fixed pseudogenes. About 60 olfactory receptor pseudogenes are relatively recent mutations that segregate in human populations—meaning that people may inherit a functional or nonfunctional copy of the olfactory receptor gene from each parent. This loss of olfactory receptors in human evolution corresponded with the acquisition of full-color vision and a highly developed cerebral cortex. This suggests that sight and reasoning have replaced roles played by olfaction in other mammals—such as finding food, marking territories, and identifying mates.

Olfaction has become so secondary to humans that we have only about 350 functional olfactory receptors, compared with about 1,100 in dogs. Practically speaking, my terrier Harley has 3 times as many olfactory receptors as any of the Nobel Prize winners who worked out the molecular mechanics of smell! The vastly increased combinatorial power of over 700 additional olfactory receptors explains why the world, indeed, smells so good to him.

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