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Olfaction - A Review
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Olfaction - Page 1

General Physiology of Olfaction

Trigeminal Sense in the Olfactory Epithelium

Olfaction - Page 2

The Odorant Binding Proteins

Odorant receptors

The Cellular Membrane

Olfaction - Page 3

G-Protein Coupled Receptors


The cAMP Transduction Cascade

Ion Protein Channels

Other Second Messengers in Olfaction - cGMP, IP3, NO, CO

Olfaction - Page 4

Chemical Olfactory Stimulation - Theories on Olfaction

The Steric Theory of Odor

The Vibrational Theory of Odor

Vibrational Induced Electron Tunneling Spectroscope Theory

Ribonucleotides as the Odorant carrier?

Olfaction - Page 5

Recent Events in Olfactory Understanding

A Combinatorial Process for odor Interpretation

Combinatorial Process Visualization

Human Olfactory Receptor Genes

Enantiomeric Specificity in the Olfactory bulb

Download this paper as a pdf file


Olfaction-Page 4

John C. Leffingwell, Ph.D.

Chemical Olfactory Stimulation - Theories on Olfaction

Over the years a number of theories relating odorant quality to molecular structure have been proposed. Here we will review the two most prominent theories and add another involving the direct participation of certain neurotransmitters or their hydrolysates in assisting the docking of odorant molecules with the olfactory receptor protein.


The Steric Theory of Odor

In 1946, future Nobel laureate, Linus Pauling26 indicated that a specific odor quality is due to the molecular shape and size of the chemical. Similarly, in the book, "Molecular Basis of Odor" by John Amoore27, he extended the idea of a "Steric Theory of Odor" originally proposed by R.W. Moncrieff in 194928 that stated air borne chemical molecules are smelled when they fit into certain complimentary receptor sites on the olfactory nervous system. This "lock and key" approach was an extension from enzyme kinetics. Amoore proposed primary odors (ethereal, camphoraceous, musky, floral, minty, pungent and putrid). The molecular volume and shape similarity of various odor chemicals were compared (by making hand prepared molecular models and physically measuring volume and creating silhouette patterns - there were no computer molecular modeling programs in that era).

The steric theory is well suited to the idea that the odorant receptor proteins accept only certain odorants at a specific receptor sites. The receptor is then activated ( by conformation deformation?) and couples to the G-protein and the signal transduction cascade begins.

The Vibrational Theory of Odor

In 1938, Dyson29 suggested that the infrared resonance (IR) which is a measurement of a molecules vibration might be associated with odor. This idea was popularized by R.H. Wright in the mid 1950’s as infrared spectrophotometers became generally available for such spectral measurements which Wright was able to correlate with certain odorants.30

During the 60’s and early 70’s, vigorous debate raged as to the validity of each theory for classifying chemical odorants.

By the mid-70’s, it appeared that Wright’s theory had failed a critical test. The optical enantiomers of Menthol31 and of Carvone32 smelled distinctly different, although the corresponding infrared spectra were identical. And this theory fell from favor. Recently (August 2001), Leffingwell has published on the internet an extensive site that provides over 100 enantiomeric pairs of odorants that have differing odor properties. This site provides both 2-D and 3-D molecular structures along with odor descriptors, odor thresholds and original references.

Vibrational Induced Electron Tunneling Spectroscope Theory

Until the seminal dissertation of Luca Turin33 in 1996, the vibrational theory had been placed under a very dark cloud. Turin, however, has attempted to provide a detailed and plausible mechanism for the biological transduction of molecular vibrations that, while not accepting the mechanical vibrational spectroscopy theory previously proposed, replaces it with a theory that the receptor proteins act as a "biological spectroscope". What was proposed is a process called "inelastic electron tunneling". Since this paper, which appeared in Chemical Senses in 1996 is available for downloading off the Internet [at http://chemse.oxfordjournals.org/content/21/6/773.full.pdf ], I will only outline the process of electron transfer proposed.

Suffice it to say that the receptor is triggered by an odorant in the presence of NADPH (ß-Nicotinamide Adenine Dinucleotide Phosphate, Reduced Form), which is formed by the enzymatic reduction of ß-Nicotinamide Adenine Dinucleotide Phosphate (NADP). NADPH is widely distributed in living matter and acts as an enzyme cofactor. ß-NADPH is a product of the pentose phosphate pathway, a multifunctional pathway whose primary purpose is to generate reducing power in the form of ß-NADPH. ß-NADPH transfers H+ and 2e- to oxidized precursors in the reduction reactions of biosynthesis. Thus, ß-NADPH cycles between catabolic and biosynthetic reactions and serves as the carrier of reducing power in the same way that ATP serves as the carrier of energy.34

NADPH (as Sodium salt)


Since according to Turin’s theory the receptor functions as an "NADPH diaphorase", it may be significant that high levels of diaphorase activity have been detected in olfactory receptor neurons.35

In order for such electron transfer to occur, Turin proposes from molecular modeling that a zinc binding site is present both on the odorant receptor protein and the G-protein. Zinc’s involvement in olfaction, its ability to form bridges between proteins, its presence in electron transfer enzymes, such as alcohol dehydrogenase and the presence of a the redox-active amino acid cysteine in the receptor’s zinc-binding motif all point to a possible link between electron flow and G-protein transduction. "Suppose the zinc-binding motif on the olfactory receptor is involved in docking to the olfactory G-protein g(olf), and that the docking involves formation of a disulfide bridge between receptor and G-protein. One would expect to find on g(olf) the other half of a zinc coordination site, for example two histidines in close proximity, and a cysteine nearby." A search in the primary sequence of g(olf) finds the motif (His-Tyr-Cys-Tyr-Pro-His). This motif has the requisite properties for docking. It is exposed on the surface of the G-protein and is known to interact with G-protein coupled receptors. In the closely-related adrenergic receptors, a role for cyclic reduction and oxidation of disulfide bridges has been suggested (Kuhl, 1985)36 . It involves cross-linking of the G-protein to the receptor by an S-S bridge which is then reduced upon binding of the (redox-active) catecholamine to the receptor, thereby releasing the G-protein. Turin proposes that a similar mechanism may be at work in olfaction.

Electron tunneling basically is the transfer of electrons down the backbone of the protein and here this would only occur as follows:

"When the (olfactory) receptor binding site is empty, electrons are unable to tunnel across the binding site because no empty levels are available at the appropriate energy. The disulfide bridge between the receptor and its associated G-protein remains in the oxidized state. When an odorant (here represented as an elastic dipole) occupies the binding site, electrons can lose energy during tunneling by exciting its vibrational mode. This only happens if the energy of the vibrational mode equals the energy gap between the filled and empty levels. Electrons then flow through the protein and reduce the disulfide bridge via a zinc ion, thus releasing the G-protein for further transduction steps.

If there is a molecule between the electron source and electron sink, and if that molecule vibrates then (taking the energy of the vibrational quantum as E) indirect tunneling can occur by an additional channel if there is an energy level in the source with energy E above that in the sink. After tunneling, the molecule will have a vibrational energy higher by E. In other words, tunneling occurs only when a molecular vibrational energy E matches the energy difference between the energy level of the donor and the energy level of the acceptor. The receptor then operates as a spectrometer which allows it to detect a single well-defined energy, E . If the change in energy between donor and acceptor levels is sufficiently large, tunneling current flows across the device only when a molecule with the appropriate vibrational energy is present in the gap. If there are several vibrational modes, which one(s) get excited will depend on the relative strengths of the coupling, and that may be expected to depend, among other things on the partial charges on the atoms and the relative orientation of the charge movements with respect to the electron tunneling path."33

While Turin’s theory has not been validated, it seems quite plausible. However, even if generally valid, it does not necessarily mean that the "Steric Theory" doesn’t play a role.

[The so-called electron tunneling concept in proteins is a major topic of debate as to the exact mechanism of electron transfer. This stems from the work of Jacqueline Barton (Electron transfer between metal complexes bound to DNA: is DNA a wire?) at the California Institute of Technology.37 ]37a

While both the "Steric" and "Vibrational Induced Electron Tunneling Spectroscope" theories answer many of the questions posed, as one is solved, others arise.

Ribonucleotides as the Odorant carrier?

It is now obvious, perhaps, that a multiplicity of events occur in olfaction. But several major questions that have not been addressed remain to be answered.

1. Are certain neurotransmitters (or their hydrolysates) involved not just as so-called "second messengers" in the transduction cascade, but are they also involved as "Amplifiers" that help to capture the odorant molecules and direct them to the receptor sites?

2. Are the ribonucleotides (AMP, cAMP, GMP and cGMP), [as well as possibly IP3], the glue that helps to bind odorants into the odorant receptor sites?

While there are a few intriguing clues in the literature relative to these questions, it appears that the potentially powerful electrostatic affinity properties of some of these neurotransmitters (or their hydrolysates) may possibly play a significant role early in the olfactory process.

In the chemoreception of "taste", it has long been known that certain ribonucleotides (especially 5’-guanosine monophosphate [5’-GMP] and 5’-inosine monophosphate [5’-IMP]) have potent synergistic effects with MSG (monosodium glutamate)38 including a significant lowering of the MSG threshold level. In 1980, Torii and Kagan showed that a several-fold enhancement of binding of glutamate occurred with bovine taste papillae in the presence of certain 5'-ribonucleotides (e.g., 5'-GMP, 5'-IMP) but not with others (e.g., 5’AMP).39

Now it should be noted that 5’-IMP and 5’-GMP (as their sodium salts) commercially are used extensively as flavor enhancers, especially for meat and fish products to enhance meaty, brothy and the "uamani" character (often in conjunction with MSG to take advantage of the synergistic flavor enhancement).

It has also been observed that there is a large synergism was observed between MSG and two species of nucleotides (GMP and IMP) in most mongrel dogs40 and between MSG and three species of nucleotides (GMP, IMP, and AMP) in beagles. This has also been observed for GMP and glutamate in mice.41

Chemically, it should also be noted that 5’-inosine monophosphate is the product of enzymatic deamination of 5’-adenosine monophosphate. For example, In meat extracts, after slaughter, there is as rapid transformation of 5’-ATP to 5’-AMP to 5’-IMP.

In olfaction, very few studies are available that show activity of these ribonucleotides in enhancing olfaction. However, Getchell has demonstrated that 8-Bromo-cAMP applied to the ciliated side of the mucosa of the bullfrog caused a concentration-dependent, reversible increase in the basal short-circuit current, but not when it was applied to the submucosal side. Pulses of 8-Bromo-cAMP and odorant presented simultaneously resulted in currents that added nonlinearly.42

In addition, 5'AMP odorant binding sites on the dendrites of the olfactory receptor neurons in the sensilla of the spiny lobster are distributed along the entire dendritic region that is exposed to odorants. The distribution of these 5'AMP binding sites is considered much more extensive than that of enzymes that inactivate 5’-AMP.43

The few implications of ribonucleotides to playing an active part in what I will refer to as the extracellular side if the receptor neurons in the mucosa has largely been overlooked probably due to two factors: (1.) the ribonucleotides are largely water soluble and have not been examined as possibly complexing with lipid odorants and (2.) researchers have focused on the intracellular second messenger activity of such compounds.

Results in our laboratory using molecular modeling and molecular fitting programs, however, show that 5’AMP, 5’cAMP, 5’GMP, 5’cGMP and IP3 all demonstrate dramatic electrostatic affinity for fitting with many odorants. For example, when compared to fitting with 5’-ATP, 5’-ADP, 5’-GTP or 5’GDP, the [computed] electrostatic fitting energy is of an order of magnitude 105 - 106 more favored. In addition, with certain odorants in a related series that have similar odor properties, we see similar fitting patterns for certain conformers [An explanation of conformers will follow in a subsequent update]. These observations are intriguing, since, if such electrostatic forces assist the odorant via some sort of complex in fitting into the receptor…this may be a "first" step in the transduction process.


26. Pauling, L., Molecular architecture and Biological Reactions, Chem. Eng. News, 24, 1375 (1946); referenced by Ohloff, G., Scent and Fragrances, Springer-Verlag, Berlin Heidelberg, 1994

27. Amoore, J.E., Molecular Basis of Odor, C.C. Thomas, Pub., Springfield (1970)

28. Moncrieff, R.W., What is Odor. A New Theory, Am. Perfumer, 54: 453 (1949)

29. Dyson, G.M., The Scientific Basis of Odor, Chem. Ind., 57: 647-651 (1938)

30. Wright, R.H., The Sense of Smell, CRC Press, Boca Raton, FL (1982)

31. Leffingwell, J.C., comment in Gustation and Olfaction, G. Ohloff and A. Thomas, Ed., Academic Press, NY, 1971, p. 144

32. Langenau, E.E., Olfaction and Taste, Vol. III., C. Pfaffman, Ed., Rockefeller University Press, New York (1967); although this fact had been known to perfumers and flavorists 50 years earlier.

33. Turin, L., A spectroscopic mechanism for primary olfactory reception. Chem. Senses, 21, 773-791 (1996)

34. Wood, W. B., et.al., Editors, Biochemistry A Problems Approach, , W. A. Benjamin, Inc., p. 195.

35. Zhao, H.; S. Firestein; C.A. Greer, NADPH-diaphorase localization in the olfactory system. Neuroreport., 6(1): 149-52 (1994)

36. Kuhl, P.W., A redox cycling model for the action of beta-adrenoceptor agonists., Experientia. 41: 1118-22 ( 1985)

37. Stemp, E.D. and J.K. Barton, Electron transfer between metal complexes bound to DNA: is DNA a wire?, Met. Ions Biol. Syst. 33:325-365 (1996)

37a. Wilson, E.K., DNA's conductance still confounds, Chem. Eng. News, July 27, 51-54 (1998)

38. Solms, J. Nonvolatile compounds and flavor, in Gustation and Olfaction, G. Ohloff and A. Thomas, Editors, Academic Press, 1971, pp.94-95.

39. Torii, K., R.H. Cagan., Biochemical studies of taste sensation. IX. Enhancement of L-[3H]glutamate binding to bovine taste papillae by 5'-ribonucleotides., Biochim. Biophys. Acta, Feb 7;627(3):313-323 (1980).

40. Kumazawa, T. and K. Kurihara, Large synergism between monosodium glutamate and 5'-nucleotides in canine taste nerve responses, Am. J. Physiol., Sep;259(3 Pt 2):R420-R426 (1990)

41. Ninomiya, Y., S. Kurenuma, T. Nomura, H. Uebayashi, H. Kawamura, Taste synergism between monosodium glutamate and 5'-ribonucleotide in mice, Comp. Biochem. Physiol. A;101(1):97-102 (1992)

42. Persaud, K.C., G.L. Heck, S.K. DeSimone, T.V. Getchell, J.A. DeSimone., Ion transport across the frog olfactory mucosa: the action of cyclic nucleotides on the basal and odorant-stimulated states. Biochim Biophys Acta, Sep 15;944(1):49-62 (1988).

43. Blaustein, D.N., R.B. Simmons, M.F. Burgess, C.D. Derby, M. Nishikawa, K.S. Olson, Ultrastructural localization of 5'AMP odorant receptor sites on the dendrites of olfactory receptor neurons of the spiny lobster. J Neurosci.; Jul;13(7):2821-2828 (1993)


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