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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 5

John C. Leffingwell, Ph.D.

Recent Events in Olfactory Understanding

A Combinatorial Process for odor Interpretation:

In March 1999, Linda Buck and Bettina Malnic at Harvard Medical School, and Junzo Hirono and Takaaki Sato at the Life Electronics Research Center in Amagasaki, Japan appear to have unravelled the mystery of how can the nose can interpret a plethora of different odors.44

It appears that the sense of smell in mammals is based on a combinatorial approach to recognizing and processing odors. Instead of dedicating an individual odor receptor to a specific odor, the olfactory system uses an "alphabet" of receptors to create a specific smell response within the neurons of the brain. As in language (or music), the olfactory system appears to use combinations of receptors (analogous to words or or musical notes, or to the way that computers process code) to greatly reduce the number of actual receptor types actually required to convey a broad range of odors.

As in genetic code where the four nucleotides (adenine, cytosine, guanine and thymine) allow the creation of a nearly infinite number of genetic combinatorial sequences, the findings of Buck et. al. provides the first confirmation that the nerves that constitute the mammalian olfactory system also use a combinatorial approach.

When an odor excites a neuron, the signal travels along the nerve cell's axon and is transferred to the neurons in the olfactory bulb. This structure, located in the very front of the brain, is the clearinghouse for the sense of smell. From the olfactory bulb, odor signals are relayed to both the brain's higher cortex, which handles conscious thought processes, and to the limbic system, which generates emotional feelings.

In the reported study, individual mouse neurons were exposed to a range of odorants. Using a technique called calcium imaging, the researchers detected which nerve cells were stimulated by a particular odor. (When an odorant molecule binds to its odor receptor, calcium channels in the membranes of the nerves open and calcium ions pour inside. This generates an electrical charge that travels down the axon as a nerve signal. Calcium imaging measures this influx of calcium ions). Using this technique, it was shown that (1) single receptors can recognize multiple odorants (2) a single odorant is typically recognized by multiple receptors and (3) that different odorants are recognized by different combinations of receptors thus indicating that the olfactory system uses a combinatorial coding scheme to encode the identities of odors. This explains how 1,000 or so receptors can describe many thousands of different odors. Buck and her colleagues also demonstrated that even slight changes in chemical structure activate different combinations of receptors. Thus, octanol smells like oranges, but the similar compound octanoic acid smells like sweat. Similarly, it was found that large amounts of a chemical bind to a wider variety of receptors than do small amounts of the same chemical. This may explain why a large whiff of the chemical indole smells putrid, while a trace of the same chemical smells flowery.

Combinatorial Process Visualization

For a novel "Shockwave" visualization of the "Combinatorial Process" that illustrates how odor molecules fit into scent receptors Click here. Note that, as with a chord played on a piano, some smells are triggered by a combination of different parts of the same odor molecule fitting into different receptors. (To view this you will need the Adobe Shockwave Player-which you can download from HERE.)

Human Olfactory Receptor Genes

On page 2 of this review, we describe briefly the recent identification & structural elucidation of human olfactory receptor genes by Lancet and co-workers12h at the Weizmann Institute of Science Crown Human Genome Center in Israel which is now publicly availabe in the HORDE online database and the sophistcated work of Zozulya and co-workers at Senomyx in which the latter describe the identification and physical cloning of 347 putative human full-length odorant receptor genes that they believe represent essentially the complete repertoire of functional human odorant receptors.12f Peter Mombaerts has recently also reviewed this subject67.

The Human Vomeronasal Organ

The VNO has been known to be present in human fetuses and has been reported sporadically in adults since the eighteenth century, although many find this improbable. Most of the work on vomeronasal function has been in rodents, snakes and insects where pheromonic chemicals play a communication role in attraction & reproduction. Its presence and function (if it, indeed, functions) in humans has been a matter of debate. Recently, however, Savic et. al. have shown that women smelling an androgen-like compound activate the hypothalamus, with the center of gravity in the preoptic and ventromedial nuclei. Men, in contrast, activate the hypothalamus (center of gravity in paraventricular and dorsomedial nuclei) when smelling an estrogen-like substance. This sex-dissociated hypothalamic activation suggests a potential physiological substrate for a sex-differentiated behavioral response in humans.69 Whether this provides indirect (or direct) evidence of VNO like descrimination in humans remains to be seen.

Recently, Mombaerts, Greer and co-workers70, showed that the human genome contains at least one gene found in epithelial tissue in the nasal that closely resembles a family of mouse pheromone receptors—genes that are primarily involved in detecting odorless chemicals such as pheromones. "Until this report," Greer states, "the consensus was that humans do not have receptors that belong to this family of genes. Now the door is open to reconsidering the functional organization of the human olfactory system." Mombaerts doesn't rule out the possibility that more pheromone receptors will turn up in sequence data in the future, but he is confident that only a few more, if any, will emerge.

Enantiomeric Specificity in the Olfactory bulb

It is well accepted that in humans certain specific chemical enantiomers (optical anti-podes) (such as carvone, menthol, limonene, linalool, citronellol, 7-hydroxy citronellol, 1-octen-3-ol, delta-decalactone, gamma-decalactone, 2-methyl-4-propyl-1,3-oxathiane, p-menthene-8-thiol, nootakatone, patchoulol, alpha-damascone, alpha-ionone, 3-mercapto-2-methylpentanol, (E)- & (Z)-nerolidols, alpha-phellandrene, alpha-terpineol, the theaspiranes, the 2 isomeric & 4 chiral forms of whiskey lactone, 2-ethylhexanoic acid, cis-rose oxide, nerol oxide, ethyl 2-methylbutyrate, methyl 2-methylbutyrate, Jasmine lactone, ethyl 2-oxo-3-methylpentanoate, 2-methylbutyric acid, 2,4,6-trimethyl-4-phenyl-1,3-dioxane, methyl dihydrojasmonate, the1-(2',2',6'-trimethyl-1'-cyclohexyl)-3-hexanols, 2-ethyl-4,4-dimethyl-1-cyclohexanone, 2,5,6-trimethyl-2-heptanol, 2-methyl-4-(2',2',3'-trimethyl-3'-cyclopenten-1'-yl)-4-pentenenitrile, the 2-methyl-4-(2',2',3'-trimethyl-3'-cyclopenten-1'-yl)-4-penten-1-ols, the 3,3-dimethyl-5-(2',2',3'-trimethyl-3'-cyclopenten-1'-yl)-4-pen ten-2-ols, the 5,6,7,8-tetrahydro-3,5,5,6,7,8,8-heptamethyl-2-naphthalenecarbaldehydes, the 5,6,7,8-tetrahydro-3,5,5,6,7,8,8-heptamethyl-2-naphthalenecarbonitriles, 2-ethyl-4-(2,2,3-trimethylcyclopent-3-en-1-yl)-2-buten-1-ol , the ambroxides) can be distinguished as they possess varying degrees of olfactory differences.54 Recently, Rubin & Katz have shown that apparently the rat is able to discriminate a wide variety of enantiomers that are indistinguishable to humans.55 Enantioselectivity of odor perception in honeybees has also recently been studied, but gave results more similar to human discrimination.56 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.

The olfactory receptor gene superfamily of the mouse

As mentioned on page 2 of this review, in the January 22, 2002 issue of Nature Neuroscience12j, Stuart Firestein with Xinmin Zhang at Columbia University identified the mouse OR genes from the nearly complete Celera mouse genome by a comprehensive data mining strategy. They found 1,296 mouse OR genes (including 20% pseudogenes). Human ORs cover a similar 'receptor space' as the mouse ORs, suggesting that the human olfactory system has retained the ability to recognize a broad spectrum of chemicals even though humans have lost nearly two-thirds of the OR genes as compared to mice.

3-D Models of selected Human olfactory receptors - determination of the putative odorant binding cavities

In February 2002, Leffingwell & Associates announced the release of theoretical 3-D Models of selected Human Olfactory receptors and a rapid and simple methodology for determining the putative odorant binding cavity. The press release may be viewed here.


Recent Publications of interest:

44. Malnic B, Hirono J, Sato T, Buck LB; Combinatorial receptor codes for odors. Cell, Mar 5;96(5):713-23 (1999): http://www.hhmi.org/news/buck.htm

45. Doty, R.L., Olfaction., Annual Rev. Psychol., 52: 423-452 , 2001; A review focusing on recent progress made in understanding olfactory function, emphasizing transduction, measurement, and clinical findings.

46. Qureshy A, Kawashima R, Imran MB, Sugiura M, Goto R, Okada K, Inoue K, Itoh M, Schormann T, Zilles K, Fukuda H, Functional mapping of human brain in olfactory processing: a PET study., J. Neurophysiol., Sep: 84(3):1656-66, 2000

46. Frank Zufall and Trese Leinders-Zufall , The Cellular and Molecular Basis of Odor Adaptation, Chem. Senses 25: 473-481, 2000 http://chemse.oupjournals.org/cgi/content/full/25/4/473

47. Wise PM, Olsson MJ, Cain WS, Quantification of odor quality., Chem Senses Aug; 25(4):429-43, 2000, http://chemse.oupjournals.org/cgi/content/full/25/4/429

48. Gomez G, Rawson NE, Cowart B, Lowry LD, Pribitkin EA, Restrepo D, Modulation of odor-induced increases in [Ca(2+)](i) by inhibitors of protein kinases A and C in rat and human olfactory receptor neurons., Neuroscience, 98(1):181-9, 2000

49. Gibson AD, Garbers DL, Guanylyl cyclases as a family of putative odorant receptors., Annual Rev. Neurosci., 23:417-39, 2000

50. Hopfield JJ, Odor space and olfactory processing: collective algorithms and neural implementation., Proc Natl Acad Sci U S A Oct 26;96(22):12506-11, 1999

51. Mombaerts P, Seven-transmembrane proteins as odorant and chemosensory receptors., Science 1999 Oct 22;286(5440):707-11, A Review.

52. Mombaerts P, Odorant receptor genes in humans., Curr Opin Genet Dev 1999 Jun;9(3):315-20; A review (genes & pseudogenes)

53. Araneda RC, Kini AD, Firestein S, The molecular receptive range of an odorant receptor, Nat Neurosci 2000 Dec;3(12):1248-55

54. J.C. Leffingwell, Chirality & Odour Perception; and Flavor-Base 2001

55. Rubin, BD & Katz, LC, Spatial coding of enantiomers in the rat olfactory bulb, Nat Neurosci 2001 Apr;4(4):355-6

56. Laska M & Galizia CG, Enantioselectivity of odor perception in honeybees (Apis mellifera carnica), Behav Neurosci 2001 Jun;115(3):632-9

57. Rogers ME & Firestein SJ., Unlocking the DOR code, Neuron. 2001 May;30(2):537-52

58. Nef P, How We Smell: The Molecular and Cellular Bases of Olfaction, News Physiol Sci 1998 Feb;13:1-5

59. Frings S, Chemoelectrical signal transduction in olfactory sensory neurons of air-breathing vertebrates, Cell Mol Life Sci 2001 Apr;58(4):510-9

60. Glusman G, Yanai I, Rubin I, Lancet D., The complete human olfactory subgenome, Genome Res. 2001 May;11(5):685-702

60a. Glusman G, Sosinsky A, Ben-Asher E, Avidan N, Sonkin D, Bahar A, Rosenthal A, Clifton S, Roe B, Ferraz C, Demaille J, Lancet D., Sequence, structure, and evolution of a complete human olfactory receptor gene cluster, Genomics 2000 Jan 15;63(2):227-45

61. Zufall F & Munger SD, From odor and pheromone transduction to the organization of the sense of smell, Trends Neurosci 2001 Apr;24(4):191-3

62. Bajgrowicz JA & Frater G, Chiral recognition of sandalwood odorants, Enantiomer 2000;5(3-4):225-34

63. Buck LB, The molecular architecture of odor and pheromone sensing in mammals, Cell. 2000, Mar 17;100(6):693-702

64. Mombaerts P, Molecular biology of odorant receptors in vertebrates, Annu Rev Neurosci 1999;22:487-509

65. Zhao H, Firestein S, Vertebrate odorant receptors, Cell Mol Life Sci 1999 Nov 15;56(7-8):647-59

66. Araneda RC, Kini AD, Firestein S, The molecular receptive range of an odorant receptor, Nat Neurosci 2000 Dec;3(12):1248-55

 67. Peter Mombaerts, THE HUMAN REPERTOIRE OF ODORANT RECEPTOR GENES AND PSEUDOGENES, Annual Rev. Genomics Hum. Genet. 2001. 2:493-510.

68. Rouquier S, Blancher A, Giorgi D., The olfactory receptor gene repertoire in primates and mouse: evidence for reduction of the functional fraction in primates, Proc Natl Acad Sci U S A 2000 Mar 14;97(6):2870-4

69. Savic I, Berglund H, Gulyas B, Roland P., Smelling of odorous sex hormone-like compounds causes sex-differentiated hypothalamic activations in humans, : Neuron 2001 Aug 30;31(4):661-8

70. Rodriguez I, Greer CA, Mok MY, Mombaerts P., A putative pheromone receptor gene expressed in human olfactory mucosa, Nat Genet 2000 Sep;26(1):18-9


 Last Updated on February 14, 2002

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