MICROSCOPY RESEARCH AND TECHNIQUE 58:135–141 (2002)

Odor Discrimination by G Protein-Coupled Olfactory

Receptors
KAZUSHIGE TOUHARA
Department of Integrated Biosciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba 277-8562, Japan

KEY WORDS olfaction; odorant; olfactory receptor; olfactory neuron; G proteins; cAMP; calcium
imaging
ABSTRACT The vertebrate olfactory system possesses a remarkable capacity to recognize and
discriminate a variety of odorants by sending the coding information from peripheral olfactory
sensory neurons in the olfactory epithelium to the olfactory bulb of the brain. The recognition of
odorants appear to be mediated by a G protein-coupled receptor superfamily that consists of ⬃1%
of total genes in vertebrates. Since the first discovery of the olfactory receptor gene superfamily in
the rat, similar chemosensory receptors have been found in various species across different phyla.
The functions of these receptors, however, had been uncharacterized until the recently successful
functional expression and ligand screening of some olfactory receptors in various cell expression
systems. The functional cloning of odorant receptors from single olfactory neurons allowed for the
identification of multiple receptors that recognized a particular odorant of interest. Reconstitution
of the odorant responses demonstrated that odorant receptors recognized various structurally-
related odorant molecules with a specific molecular receptive range, and that odor discrimination
is established based on a combinatorial receptor code model in which the identities of different
odorants are encoded by a combination of odorant receptors. The receptor code for an odorant
changes at different odorant concentrations, consistent with our experience that perceived quality
of an odorant changes at different concentrations. The molecular bases of odor discrimination at the
level of olfactory receptors appear to correlate well with the receptive field in the olfactory bulb
where the input signal is further processed to create the specific odor maps. Microsc. Res. Tech. 58:
135–141, 2002. © 2002 Wiley-Liss, Inc.

INTRODUCTION ture. The olfactory system not only discriminates the

Sensation and perception consist of five major mo-
dalities: visual, auditory, olfactory, gustatory, and so-
matic sensory systems. These sensory systems perceive
information from the external environment through
peripheral neurons that express specific sensory recep-
tors and transmit the information to the central ner-
vous system. The combination of sensory neuron spec-
ificity and the pattern of firing activity appears to con-
tribute to reconstruction of the information into a
unified conscious perception in the central regions. The
French poet, Charles Baudelaire, described in his Cor-
respondances how well all smells, colors, and sounds
correspond to each other (“Les parfums, les couleurs et
les sons se repondent.”) Apparently, the perception of
external signals and the correspondence of those sig-
nals in the physical world we live in, is essential for
most species across phyla to organize their various
behaviors and processes to survive.
In vision, color discrimination is produced by appro-
priate combinations of three types of receptors that are
each most sensitive to a different part of the visible
spectrum (i.e., red, blue, and green) (Nathans, 1987). In
gustatory sensation, five basic qualities (i.e., bitter,
salty, sour, sweet, and umami) are detected by distinct
classes of receptors in taste cells (Lindemann, 1996).
Unlike visual and taste systems, the olfactory system
requires highly discriminative capabilities to distin-
guish thousands of different odorous chemicals in na-
odor quality, but also perceives a change in quality of
an odorant at different concentrations (Beets, 1970;
Polak, 1973). The detection and discrimination of a
variety of odorant molecules are, therefore, established
by sophisticated functional organization that begins at
the olfactory epithelium in the nose where a variety of
odorant molecules are detected, and ends at the higher
cortical areas of the brain where a perception is con-
structed.
The first clue for understanding molecular mecha-
nisms of olfactory signal transduction was derived from
biochemical evidence for the involvement of second
messenger pathways (Kurihara and Koyama, 1972;
Nakamura and Gold, 1987; Pace et al., 1985; Sklar et
al., 1986), which led to an assumption that G protein-
coupled receptors likely mediated the odorant signals
in the olfactory epithelium. The hypothesis was proved
by the identification of a multigene family encoding
*Correspondence to: Kazushige Touhara, Department of Integrated Bio-
sciences FSB201, Graduate School of Frontier Sciences, The University of Tokyo,
Chiba 277-8562, Japan. E-mail: touhara@k.u-tokyo.ac.jp
Received 26 February 2001; accepted in revised form 19 June 2001
Grant sponsor: Ministry of Education, Science, Sports, and Culture; Grant
sponsor: Ministry of International Trade and Industry; Grant sponsor: NOVARTIS
Foundation for the Promotion of Science; Grant sponsor: The Tokyo Biochemical
Research Foundation.
DOI 10.1002/jemt.10131
Published online in Wiley InterScience (www.interscience.wiley.com).

© 2002 WILEY-LISS, INC.

136 K. TOUHARA
Fig. 1. Schematic diagram illustrating the coronal sections of a
mouse nose. A nasal cavity is shown white, and the black region
represents turbinate. The olfactory epithelium covers the surface of
turbinate where the olfactory sensory neurons are located. Shown
(middle) is a schematic diagram of an olfactory sensory neuron. An
odorant signal transduction cascade is also shown (bottom). The bind-
ing of an odorant to a G protein-coupled olfactory receptor activates
stimulatory G protein (Golf) and type III adenylyl cyclase (ACIII),
resulting in a cAMP increase followed by an opening of cyclic nucle-
otide-gated channel and influx of cations.
putative odorant receptors by Buck and Axel (1991)
(Fig. 1). The putative odorant receptors expressed in
the peripheral neurons belong to a family of seven
transmembrane G protein-coupled receptors, which ap-
pears to consist of approximately 1% of the total genes
in rodents (Mombaerts, 1999a,b). This large receptor
repertoire has been identified not only in vertebrates
but also in invertebrate species such as the nematode
(Bargmann, 1998; Troemel et al., 1995; Troemel, 1999)
and the fruit fly (Clyne et al., 1999; Gao and Chess,
1999; Vosshall et al., 1999), suggesting that an evolu-
tionary process aimed at creating diversity in order to
establish the remarkable discriminatory capacity of
chemosensory system (Dryer, 2000). This review fo-
cuses on recent progress in deciphering functional
properties of the vertebrate odorant receptors, which
appear to be responsible for odor discrimination in the
olfactory system, and also concerns molecular mecha-
nisms by which slight alterations in odorant structure
or concentration result in changes in perceived odor
quality.
ODORANT RESPONSES OF
OLFACTORY NEURONS
Electrophysiological techniques allowed for the re-
cording of functional responses of single olfactory neu-
rons in which action potentials are generated upon
exposure to various odorants (Firestein, 1996; Kura-
hashi and Gold, 2000). Numerous data collected from
amphibians have suggested that each olfactory neuron
can recognize and respond to a variety of structurally
different odorant molecules, while a single odorant can
activate multiple neurons with different response in-
tensities that depend on odorant concentrations (Duch-
amp-Viret and Duchamp, 1997). The qualitative tuning
of olfactory neurons with broad molecular ranges indi-
cated that the encoding of an odorant was determined
by a unique set of olfactory neurons that responded to
the odorant. Recent studies on rat olfactory receptor
neurons also demonstrated that individual olfactory
neurons are responsive to qualitatively distinct odor
compounds and that the broad tuning of olfactory neu-
rons with overlapping odorant response profiles allow
for the identification and discrimination of odor signals
in vertebrates (Duchamp-Viret et al., 1999) (Fig. 2A).
Calcium imaging is another strategy for detecting
physiological odorant responses of olfactory neurons by
measuring the temporal and spatial properties of Ca2⫹
changes caused by odorant stimuli (Restrepo and
Boyle, 1991; Restrepo et al., 1996; Tareilus et al., 1995)
(Fig. 2B). Odorant stimulation causes Ca2⫹ entry
through cyclic nucleotide-gated channels in individual
responsive neurons, which is regulated by a series of
signal transduction components (Breer and Boekhoff,
1992; Reed, 1992; Schild and Restrepo, 1998) (Fig. 1) as
well as feedback mechanisms followed by odor adapta-
tion of the activated cells (Boekhoff et al., 1996; Kura-
hashi and Menini, 1997; Kurahashi and Shibuya, 1990;
Wei et al., 1998; Zufall et al., 1991). The Ca2⫹ imaging
technique has allowed for the detection of elevations in
Ca2⫹ resulting from stimulation with a variety of odor-
ants in various species (Hirono et al., 1994; Restrepo et
al., 1993; Sato et al., 1994). Individual olfactory neu-
rons appear to have broad odorant tuning specificity
that is determined based on structural features in
odorant molecules such as differences in chain length,
terminal groups, and positions of functional groups.
Further, single responsive cells to a certain odorant
responded to additional odorants with increased con-
centrations. The data from both Ca2⫹ imaging and
electrophysiological studies suggested a combinatorial
receptor code model in which different odorants are
recognized by overlapping sets of olfactory receptors.
It is generally accepted that individual olfactory neu-
rons express one of a thousand olfactory receptors in
rodents (Malnic et al., 1999; Nef et al., 1992; Ressler et
al., 1993; Strotmann et al., 1992; Vassar et al., 1993).
Therefore, the functional property of the olfactory neu-
ron reflects the molecular receptive range of the odor-
ant receptor that is expressed in the neuron. Further,
the olfactory system forms a unique spatial organiza-
tion such that the axons of olfactory neurons express-
ing the same receptor converge onto fixed glomeruli
(Mombaerts et al., 1996; Ressler et al., 1994; Strot-
mann et al., 1994; Vassar et al., 1994) (Fig. 2C). These
observations suggest that the encoding of an odorant
 ODOR DISCRIMINATION BY OLFACTORY RECEPTORS 137

Fig. 2. A: A combination of odor-

ants and receptors is established in a
way that a single odorant is recog-
nized by multiple receptors and that a
single odorant receptor recognizes
multiple odorants. B: The olfactory re-
ceptor expressed in single neurons re-
sponding various odorants can be
identified by a combination of Ca2⫹
imaging and single cell RT-PCR tech-
niques (Kajiya et al., 2001; Touhara et
al., 1999). C: The olfactory system
forms a unique spatial organization.
The axons of olfactory neurons ex-
pressing the same receptor converge
onto the fixed glomeruli (top). The
specific pattern of activation is formed
in the olfactory bulb in a unique fash-
ion determined by receptor repertories
specific to each odorant (bottom). Re-
printed from Life Sciences, 68, Tou-
hara, K., Functional cloning and re-
constitution of vertebrate odorant re-
ceptors, 2199 –2206, 2001, with
permission from Excerpta Medica Inc.

determined by the type of activated receptors in the
olfactory epithelium directly reflect the receptive field
in the olfactory bulb where the input signal is further
processed to create the specific odor maps. Odor dis-
crimination, therefore, can be accounted for by a strat-
egy that uses receptor codes for various odors.
FUNCTIONAL PROPERTIES OF
OLFACTORY RECEPTORS
G protein-coupled receptors (GPCRs) constitute a
large protein family that mediates diverse physiologi-
cal stimuli such as light, hormones, and neurotrans-
mitters, and activates G protein-based transduction
cascades (Dohlman et al., 1991). The olfactory recep-
tors, which form the largest and most heterogenous
GPCR family, have been identified from chemosensory
cells of various species across phyla with little similar-
ity in sequence, but presumably with a common func-
tion, which is to detect chemicals from the extracellular
space (Mombaerts, 1999a,b). Some conserved motifs of
5–10 amino acids were identified in the sequences to
distinguish the olfactory receptors from other GPCRs
and to classify them as an olfactory receptor family.
The variable regions in the sequences of olfactory re-
ceptors were found within transmembrane domains
that might function as the ligand-binding site in a
manner similar to other GPCRs (Pilpel and Lancet,
1999; Singer et al., 1995; Singer, 2000).
Functional evidence, however, that the olfactory re-
ceptors indeed mediate odorant signals, had not been
provided for many years since the discovery of the
superfamily (Buck and Axel, 1991), most likely because
of the difficulty in functionally expressing the olfactory
receptors in heterologous expression systems (Gimel-
brant et al., 1999). The first olfactory receptor to be
paired with its cognate odor ligand was a rat olfactory
receptor I7, which was functionally expressed in rat
olfactory neuron by virtue of an adenovirus-mediated
gene transfer followed by a response assay with an
electro-olfactogram (Zhao et al., 1998). The same ap-
proach was successfully undertaken for a mouse olfac-
tory receptor MOR23 to recapitulate the odorant re-
sponse of a cell from which the receptor gene was
functionally cloned (Touhara et al., 1999). Transient
elevations in intracellular Ca2⫹ in single adenovirus-
infected cells were detected by stimulation by the li-
gand odorant molecule. The functional expression of
odorant receptors in this homologous expression sys-
tem suggests that heterologous cell systems lack some
of the factors required for odorant receptors to function
properly. Rather puzzling results, however, have been
obtained in our laboratory that not all the olfactory
receptors have been expressed functionally by using
the same approach (unpublished observations). None-
theless, the ligand specificity of I7 and MOR23 recep-
tors implied that the olfactory receptors recognized
various odorous molecules that possessed some struc-
tural similarity, consistent with a mode of ligand rec-
ognition of other GPCRs.
A heterologous expression system has been estab-
lished by using chimeric odorant receptors with a tag of
N-terminal rhodopsin sequences in HEK293 cells,
which turned out to be an efficient approach to decipher
odorant-olfactory receptor interations (Krautwurst et
al., 1998). The Ca2⫹ imaging of odorant responses of
the expressed receptors was performed in an artificial
reporter system that can detect receptor activation at
the single cell level with high sensitivity and temporal
138 K. TOUHARA
resolution by forcing the signal to the inositol-1,4,5-
triphosphate (IP3) pathway by virtue of G␣15/16 that
couples to various GPCRs. The reliability of this ex-
pression system was confirmed for I7 (Krautwurst et
al., 1998) and MOR23 (Kajiya et al., 2001), which
showed the same ligand specificity profile as that ob-
tained by the adenovirus-mediated expression system.
The chimeric receptor approach has led to the identifi-
cation of a number of ligands for several olfactory re-
ceptors in rats (Krautwurst et al., 1998), mice (Kajiya
et al., 2001; Krautwurst et al., 1998), and humans
(Wetzel et al., 1999), and most recently for a taste
receptor that recognized bitter compounds (Chan-
drashekar et al., 2000).
Araneda et al. (2000) carried out extensive ligand
screening of the rat I7 receptor to obtain a detailed
description of the odorant binding characteristics. The
molecular receptive range was such that an odorant
receptor recognized various odorants with a high spec-
ificity for certain molecular features but high tolerance
for others. The ligand specificity of mOR-EG, which
was functionally cloned from an odorant-responsive
single cell, also supported the notion that odorant re-
ceptors were able to discriminate structurally-related
odor compounds while still recognizing a wide variety
of odorant molecules (Kajiya et al., 2001). It should be
of note that an odorant receptor does not necessarily
recognize odorants with the same aroma but responds
to odorants that are similar in structure. The struc-
tural diversity of the olfactory receptor superfamily
appears to be created in order to establish the remark-
able discriminatory capacity of the chemosensory sys-
tem. Finally, although the function of olfactory recep-
tors as odorant-binding proteins has been proven, an-
other putative function of olfactory receptors in axon
guidance has yet to be elucidated (Mombaerts et al.,
1996; Wang et al., 1998).
COMBINATIONS OF ODORANTS
AND RECEPTORS
An assumption that an odorant is recognized by mul-
tiple olfactory receptors has been proven accurate by a
functional cloning approach that involved recording
responses of individual olfactory neurons exposed to a
particular odorant of interest, and cloning the ex-
pressed olfactory receptor gene(s) (Kajiya et al., 2001;
Malnic et al., 1999; Touhara et al., 1999) (Fig. 2B). This
retrospective cloning strategy is rationalized by the
belief that single mouse olfactory neurons express
mainly one olfactory receptor gene (Nef et al., 1992;
Ressler et al., 1993; Strotmann et al., 1992; Vassar et
al., 1993). A series of control experiments including
restriction enzyme analyses of PCR products proved
that one olfactory receptor gene could be amplified
from one neuron by using the single cell RT-PCR tech-
nique (Malnic et al., 1999). Thus, the two-step func-
tional cloning approach (i.e., a combination of calcium
imaging and RT-PCR techniques) allowed for the iden-
tification of a set of mouse olfactory receptors that was
responsible for the identity of a specific odorant. Among
the receptors, which were identified from cells that
responded to a series of aliphatic odorants with related
structures, some are highly homologous at the amino
acid sequence level, but others are relatively diverse in
the phylogenetic tree (Malnic et al., 1999; Touhara,
Fig. 3. Some odorant receptors recognize overlapping sets of odor-
ants with different specificity and affinity. A: The receptor A recog-
nizes an odorant 1 with a higher affinity than an odorant 2. B: The
receptor B binds an odorant 2 with a higher affinity than an odorant
1. C: The odorant 1 is recognized by the receptor A at a higher affinity
than by the receptor B or the receptor C. At a low concentration of the
odorant 1, only the receptor A recognizes the odorant 1 (a), but at
increased concentrations, more receptors can recognize the odorant
1 (b,c), implicating that the encoding of the odorant 1 changes at
different concentrations. See details in Kajiya et al. (2001).
2001). Thus, an odorant appears to be recognized by a
diverse set of odorant receptors that include two arrays
of receptors: one with high homology at the amino acid
sequence level and another exhibiting high sequence
diversity.
However, it is necessary to demonstrate that the
cloned receptors indeed reflect the functional proper-
ties of the olfactory neurons from which the receptor
was isolated. One study suggested that single olfactory
neurons might express more than one odorant receptor
gene (Rawson et al., 2000), prompting us to recapitu-
late the odorant responses in functional expression sys-
tems. The first critical control was provided for the
MOR23 gene, which was originally isolated from a cell
that responded to the floral odorant lyral (Touhara et
al., 1999), by using an adenovirus-mediated gene
transfer approach in a manner similar to that utilized
for the rat I7 receptor. Most recently, two other olfac-
tory receptors, mOR-EG and mOR-EV, have been re-
constituted in the HEK293 expression system, further
confirming that a receptor expressed in single olfactory
neurons is responsible for the physiological function of
the neurons (Kajiya et al., 2001).
Studies on the molecular receptive range of each
olfactory receptor and the functional cloning of multi-
ple receptors for a particular odorant have begun to
provide a clue for understanding how 1,000 olfactory
receptors are organized to encode the information of
thousands of different odorant molecules. A single re-
ceptor recognizes multiple odorants. A single odorant
is, in turn, recognized by multiple receptors. Since each
of the receptors recognizing a common ligand shows
different affinities to the ligand, the repertoire of the
receptors activated by an odorant changes with differ-
ent concentrations (Fig. 3) (Kajiya et al., 2001). The
homologous olfactory receptors have been shown to
 ODOR DISCRIMINATION BY OLFACTORY RECEPTORS
recognize overlapping sets of odorants with different
specificity and affinity in a reconstituted system, dem-
onstrating that a change in the concentration of an
odorant results in a change in its receptor code (Kajiya
et al., 2001). These results partly explain our experi-
ence that the quality of some odorants is perceived
differently at different concentrations. It has also been
shown that more olfactory neurons, which mean more
olfactory receptors, fire at higher concentrations of
odorants (Ma and Shepherd, 2000). Therefore, odor
discrimination appears to be established at the level of
olfactory receptors expressed in the neurons in the
olfactory epithelium.
The encoding of an odorant quality is determined by
a combination of receptors, which is set for each odor-
ant molecule. The spatial activity pattern produced in
the olfactory bulb upon odorant stimulation directly
reflects the types of activated neurons in the olfactory
epithelium. This combinatorial receptor code model is
consistent with the broad tuning properties of olfactory
neurons with overlapping odorant responsiveness.
Once the chemical signal encoded by odorants from the
outside world is converted to electrosignals in the re-
ceptor neurons, the information is transmitted as an
on-off signal to the olfactory bulb and ultimately to the
olfactory cortex. Although further sharp tuning of the
specificity and the integration of signals from odorant
receptors may occur in the olfactory bulb and cortex
(Mori et al., 1999), the pattern created at the periph-
eral receptor neurons is fairly preserved in the course
of signal processing. The receptor code scheme, there-
fore, plays the main role in contributing to the olfactory
processing of odor molecule information.
SIGNALING CASCADES IN
OLFACTORY NEURONS
The activated olfactory receptors turn on G protein-
based signal transduction cascades that lead to depo-
larization of the receptor neurons via cation influx
through cyclic nucleotide-gated channels (Breer and
Boekhoff, 1992; Reed, 1992; Schild and Restrepo, 1998)
and by Ca2⫹-activated Cl⫺-channel current (Fring et
al., 2000; Kurahashi and Yau, 1993). Since the receptor
codes for odorants seem to mainly contribute to odor
discrimination, the function of signal transmission in
olfactory neurons is mainly to produce action poten-
tials. In this context, it should not be necessary to have
more than one signal transduction pathway. Indeed,
gene knock-out studies suggested that the cAMP cas-
cade comprised of three components (i.e., stimulatory G
protein ␣ subunits G␣olf, adenylyl cyclase type III, and
cyclic nucleotide-gated channels) was dominant in
transmitting the odorant signal in the olfactory neu-
rons (Belluscio et al., 1998; Brunet et al., 1996; Wong et
al., 2000) (Fig. 1). However, some odorants activate a
cAMP cascade (as “cAMP”-elevating odorants), while
another signaling pathway has been shown to exist,
leading to an increase in IP3 (by “IP3”-elevating odor-
ants) (Breer and Boekhoff, 1992). Thus, it remains
widely debated whether the cAMP cascade mediates
signal transduction for all odorants in vertebrate olfac-
tory neurons.
In the HEK293 expression system, stimulation of
olfactory receptors by ligand odorants resulted in
cAMP increases (Kajiya et al., 2001). Kajiya et al.
139
(2001) also showed that an odorant receptor, mOR-EG,
recognized both cAMP and IP3-elevating odorants (i.e.,
eugenol and ethyl vanillin). Further, the receptors did
not couple to Gq-type G proteins that activate the IP3-
pathway (Kajiya et al., 2001). These observations are
consistent with the notion that the cAMP pathway via
G␣olf, adenylyl cyclase III, and cyclic nucleotide-gated
channels is a major signaling cascade in the olfactory
neurons. We, however, cannot rule out the possibility of
the existence of novel types of G proteins in olfactory
neurons, which couple to odorant receptors and stimu-
late the IP3 pathway. In this regard, recent observa-
tions of cross-talk between the two pathways may sug-
gest that olfactory neurons possess various regulatory
mechanisms that work in concert to process complex
odorant signals (Chen et al., 2000; Vogl et al., 2000).
This evidence may be relevant to the observation that
odorant stimulation results in either excitatory or in-
hibitory responses of individual olfactory neurons
(Ache, 1994). Nonetheless, discrimination of various
odorants seems to be performed primarily at the recep-
tor level but not at the level of signaling pathways.
CONCLUSIONS
Recent accumulated evidence has undoubtedly
proven that the protein encoded by the olfactory recep-
tor genes originally identified by Buck and Axel (1991),
mediated responses to particular odorants that shared
specific structural features. The molecular receptive
ranges of odorant receptors appear to be highly toler-
ant in some aspects, but highly specific in other as-
pects, which establishes a complex combination of odor-
ant receptors that recognize and perceive a specific
odorant. The cloning approach to identify retrospec-
tively the odorant receptor gene that individual respon-
sive neurons express, allowed for the functional char-
acterization of receptors that specifically recognized a
particular odorant of interest. This strategy allowed for
the identification of multiple odorant receptors by
which a single odorant could be potentially recognized.
Each different odorant is encoded by a unique set of
odorant receptors. The olfactory system, therefore, es-
tablishes odor discrimination by use of this encoding
mechanism in which a combination of activated odor-
ant receptors determines the odor quality. The direct
experimental evidence for this combinatorial code
model was provided by recent reconstitution studies in
which structurally-related olfactory receptors recog-
nized overlapping sets of odorants with distinct ligand
specificity and affinity (Kajiya et al., 2001).
The physiological function of each olfactory neuron
correlates well with the molecular receptive range of an
odorant receptor that is expressed in the olfactory neu-
ron. The spatial patterns of receptor expression in the
olfactory epithelium and the synaptic input into the
olfactory bulb suggest that the molecular bases of odor
discrimination at the receptor level appear to account
for the pattern formation by signal input from distinct
odorant receptors in the olfactory bulb and ultimately
in the olfactory cortex where a highly tuned odor map
is created. Information obtained by various approaches
such as electrophysiology, biochemistry, cell physiol-
ogy, and especially molecular biology, have begun to
converge, resulting in detailed molecular understand-
ing of the mechanisms underlying complex olfactory
140 K. TOUHARA
information processing (Buck, 1996; Buck, 2000; Hilde-
brand and Shepherd, 1997; Nakamura, 2000). The no-
table exception of humans, in which the olfactory re-
ceptor genes seem to comprise a large number of pseu-
dogenes, is intriguing in light of the fact that humans
exhibit relatively poor olfactory performance among
animals (Ben-Arie et al., 1994; Glusman et al, 2001;
Rouquier et al., 1998; Zozulya et al., 2001). The corre-
lation of olfaction with various illnesses such as Alz-
heimer’s disease and various other mental disorders
has been emerging as an important consideration upon
diagnosis and treatment. Unraveling the mystery of
the sense of smell will lead to rediscovery of the impor-
tance of olfaction, which has always been undervalued,
along with the almost pathological avoidance of smells
in modern human society, and ultimately will result in
helping human welfare.
ACKNOWLEDGMENTS
I thank Ms. J. Ito for English editing, lab members
for providing data and valuable advice, and many other
people for encouragement.
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