Journal of Electrostatics 70 (2012) 1e6

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Journal of Electrostatics
journal homepage: www.elsevier.com/locate/elstat

Review

Mechanism of smell: Electrochemistry, receptors and cell signaling

Peter Kovacic*
Department of Chemistry and Biochemistry, San Diego State University, 5500 Campanile Drive, San Diego, CA, USA

a r t i c l e i n f o

a b s t r a c t

Article history:
Received 15 December 2010
Accepted 21 July 2011
Available online 25 October 2011

This report presents in four main parts a novel approach based on electrochemistry, receptors and cell
signaling. In Part A, there is limited correlation between dipole moments (DMs), associated electrostatic
elds (EFs), and odor. For Part B, binding of the odorant to the receptor results in interaction of the ligand
EF with those of the protein receptor, resulting in alteration. Part C addresses passage of the message by
the altered EF to the olfactory neurons. Part D represents the nal step in which the electrical signal is
converted to perceived odor in the cerebral olfactory cortex.
2011 Published by Elsevier B.V.

Keywords:
Scent
Mechanism
Electrochemistry
Neurons
Cell signaling
Receptor

1. Introduction
Recent reviews document the contribution of important
involvement of the combination of receptors, cell signaling and
electrochemistry in many aspects of biology and medicine [1e9]. It
is reasonable to apply this approach, as an extension, to the
mechanism of scent based on extensive evidence. Although there
has been considerable research involving these elements in the
olfactory system, the proposed theory represents a novel, unifying
mechanistic framework.
The two principal prior modes of action are based on Shape and
Molecular Vibrations [10,11]. Both have been the object of much
controversy. The Shape approach appears to have lost favor over
the years. A 2002 book provides extensive limitations [12].
However, there can be no doubt that shape plays a crucial role in
receptor binding, an important aspect of the overall process. As an
elaboration of earlier suggestions, widespread data for the Vibration Theory was presented, based mainly on inelastic electron
tunneling spectroscopy [10,11]. Some of the salient features consist
of studies on enantiomers, deuterated materials, unusual correlations with thiols and boranes involving odor and spectral characteristics, ferrocene versus nickelocene and the saturated aldehyde
homologous series.
When nature nds a useful theme, it is usually made use of
repeatedly. For example, consider functional groups: amide

* Tel.: 1 619 5945595; fax: 1 619 5944634.

E-mail address: pkovacic@sundown.sdsu.edu.
0304-3886/$ e see front matter 2011 Published by Elsevier B.V.
doi:10.1016/j.elstat.2011.07.005

(protein), acetal (carbohydrate), ester (lipid), the steroid skeleton

(hormones) and the isoprene unit (terpenes and natural rubber), as
well as reaction processes, such as, involvement of electrostatics,
electron transfer, enzymes, cell signaling and reactive oxygen
species. The literature is rife with examples. The Vibration theory is
analogous to the mode of action of sight and hearing which also can
be regarded as spectral senses [10]. Hence, application to smell is
not alone. The Electrochemical theory can be devided into four
parts: (A) limited correlation of odor with dipole moments (DMs)
and electrostatic elds (EFs), (B) receptor binding followed by
interaction of the ligand EF with EFs of the receptor protein, (C)
interaction of the modied EF with the olfactory nerve, and (D)
electrochemical events in the cerebral olfactory cortex. The
unifying approach is able to rationalize most of the elements in the
vibration proposal, in addition to providing novel insight. The
framework is interdisciplinary based on interaction of elements
known to play vital roles in living systems. Since action mode is
often multifaceted, other factors may also participate.
2. Part A. odorant molecules and dipoles: limited correlation
Compounds, such as hydrogen, nitrogen and oxygen, with no
dipoles have no odors, in accord with the theoretical framework.
Chlorine reacts rapidly at the receptor to produce odorous material.
These molecules were also included in the Vibration theory [10].
Alkanes have quite small dipoles, e.g. propane (DM 0.08) (Table 1)
[13] and relatively weak odors. Natural gas (methane) is diluted
with a strong odorant in order to aid in leak detection. On the other
hand, common perfumes contain functional groups (aldehyde,

P. Kovacic / Journal of Electrostatics 70 (2012) 1e6

Table 1
Dipole moments of organic functional groups [13].
Compound

Dipole moment (DM)

Propane
cis-2-Butene
Diethyl ether
Ethylamine
Phenol
Dimethyl sulde
Ethanethiol
Ethanol
Acetic acid
Ethyl acetate
Chloromethane
Pentaborane
Acetaldehyde
Acetone
Acetamide
Acetonitrile

0.08
0.25
1.10
1.22
1.22
1.55
1.60
1.69
1.70
1.75
1.89
2.13
2.75
2.88
3.68
3.90

ketone, ester and nitrile) possessing higher DM values (1.75e3.92)

(Table 1). However, this relationship alone is not sufcient in
rationalizing the experimental data. The possible involvement of
dipoles was briey considered in the Vibration theory article:
.one might expect there to be some relationship between atomic
partial charges and the strength of an odorant. Especially, this is the
case: .groups such as ketones, nitro groups, aldehyde, nitriles and
ether links are all polar groups. This, however, cannot be the sole
reason for differences in odor strength. For example, vanillin is one
of the strongest odorants known, whereas the closely related
heliotropin is much weaker despite similar partial charges [10].
The notion that the smell of a molecule is the sum of its parts [11]
can be interpreted as the sum of the EFs from the electrostatic
standpoint. The next section provides a rationale based on the
effect of binding to receptors on altering the molecular dipoles.
A criticism of both Vibration and Electrochemistry theories is
that vibrational energies can be small as in the case with some
dipole forces (EFs) of odorant molecules. Is there sufcient energy
to produce the observed result? Electrostatic forces can be relatively weak for dipoles, but stronger for ions. However a 2008
article questions the validity of that argument. Can such low levels
have an inuence in living systems? A recent study provides
evidence for involvement. Investigators have gained insight into
physiological events in which weak forces, as low as 0.5 pN, play
a regulatory role [e.g., in ion channel functioning [14] and DNA
synthesis [15]]. The effect of small forces was studied on participation of four-armed DNA structures in DNA recombination.
Signicant impact on the conformational structures was made by
forces as weak as 0.5 pN. Therefore, it is reasonable to conclude that
electrostatic energetics can play a role in biological processes, as
suggested in our various reviews [1e9], as well as molecular
vibrations.
3. Part B. interaction of odor molecule EF with receptor EFs
An appropriate introduction to this section is the following:
The discovery of smell receptors owes almost everything to the
tenacity and intuition of a single scientist, Linda Buck. Her work,
published in 1991 caused the hitherto largely stagnant eld of smell
research to burst into renewed life [11].
It is evident that the EFs alone of molecules are insufcient to
rationalize the experimental observations. However, docking of the
molecule into the receptor site brings the molecular EFs in contact
with EFs of the receptor protein. There are many protein EFs of
varying strengths associated with the numerous functionalities
present. Some of the functional groups possess strong EFs, as with

the ions derived from acidic and basic amino acids. The most
prevalent dipole and a strong one (DM 3.68) (Table 1) is that of
the peptide (amide) bond. Alterations can occur with interactions
of dipoles or ions in the receptor, hydrogen bonding, ion formation
with volatile acids and bases and covalent bonding. Thus, molecules with identical DMs and EFs can have different odors since
binding to different receptors results in different EFs due to varied
alteration. The important aspect of change in the strength of the
odorant molecule EF eld has received scant attention previously.
The altered EF then propagates the sequence by interaction with
neurons in the olfactory system.
There is considerable information concerning the olfactory
receptors. In the mammalian olfactory system, information from
approximately 1000 different odorant receptor types is organized
into four spatial zones [16]. Each zone is a mosaic of randomly
distributed neurons expressing different receptor types. In the
olfactory bulb, the information undergoes organization into
a spatial map. The discriminatory capacity of the mammalian
olfactory system is such that thousands of volatile chemicals are
perceived as having distinct odors [17]. Odorant receptors (ORs)
were identied for molecules with related structures, but varied
odors. One OR recognizes multiple odorants and one odorant is
recognized by multiple ORs, but different odorants are recognized
by different combinations of ORs. Thus, the olfactory system uses
a combinatorial receptor coding scheme to encode odor identities.
Slight alterations in an odorant or a concentration change, can alter
its code.
The spatial distribution of odorant receptor RNAs in the mouse
olfactory epithelium were examined [18]. Topographically distinct
patterns exist of receptor RNAs suggesting that the nasal cavity is
divided into a series of expression zones. The zonal patterning may
serve as initial organizing steps in an olfactory sensory information
coding. Molecular electrostatic potential derived from repeating
phosphate groups in RNA may be a contributing factor. The
detection of chemically distinct odorants presumably results from
the association of odorous ligands with specic receptors on
olfactory sensory neurons [19]. A novel gene family may encode
diverse groups of odorant receptors. In a review, in mammals,
olfactory stimuli are detected by sensory neurons located at two
distinct sites: the olfactory epithelium (OE), located at the posterior
nasal cavity, and the vomeronasal organ (VNO), a tubular structure
that opens into the nasal cavity [20]. Whereas volatile odorants are
detected in the OE, the VNO may be specialized to detect pheromones. Sensory signals generated in both cases are transmitted
through different neural pathways in the brain. OE-derived signals
reach higher cortical centers, whereas those from the VNO are
targeted to the amygdala and hypothalamus. Each neuron appears
to express a single receptor type. Neurons expressing the same
receptor are randomly distributed on one of four spatial zones in
the OE. However, in the olfactory bulb, the axons of these neurons
converge on only a few stereotyped glomeruli. Like odorant
receptors, the VNO counterparts may be G-protein coupled. In the
OE, it appears that each odorant receptor may recognize a particular structural feature shared by many odorants and that each
odorant may be recognized by many different receptors. According
to the electrochemical theory, .a particular structural feature
shared by many odorants might be electrostatic elds associated
with the receptor-ligand complexes.
The review also addresses aspects of cell signaling. If different
receptors expressed by the same cell transduce signals via different
transduction pathways, they may function independently. There
may be crosstalk among different pathways that might provide
a basis for the integration and processing of sensory information
within an individual chemosensory neuron. An olfactory neuronspecic G-protein was identied strengthening the case for

P. Kovacic / Journal of Electrostatics 70 (2012) 1e6

a G-protein coupled mechanism of olfactory transduction [21].

Different neurons respond to different odorants, a presumed
requirement for odor discrimination. Information from different
olfactory receptors is organized in the nose as well as the next relay
in the olfactory system, the olfactory cortex.
4. Part C. receptor-ligand dipolar interaction with olfactory
neurons
The principal basis consists of electrochemical interaction of the
receptor-ligand EF with the olfactory neurons. Representative,
supporting literature is summarized. Ion gradients are the source of
electrical potentials in neurons [22]. The impulses that are carried
along axons, as signals passing from neuron to neuron, are electrical
in nature. These electrical signals occur as transient change in the
electrical potential differences (voltages) across the membrane of
neurons. Such potentials are generated by ion gradients. Nerve
impulses, also called action potentials, are transient changes in the
membrane potential that move rapidly along nerve cells. Action
potentials are created when the membrane is locally depolarized.
These small changes are enough to have a dramatic effect on
specic proteins in the axon membrane called voltage-gated ion
channels. Various electrochemical interactions occur with the
neuron system. According to the olfactory approach, EFs arising
from interaction of the odorant EF with the receptor EFs then pass
the message onto the olfactory neurons in step C of the sequence.
4.1. Electro-olfactograms
Research quite relevant to the electrochemical approach
involves electro-olfactograms (EOGS) which reect electrical
potentials of the olfactory epithelium that occur in reference to the
olfactory stimulation [23]. The EOG represents the sum of the
generator potentials of olfactory receptor neurons. This approach
has been used extensively with animals, together with a much
lesser application to humans. A review outlines the following: (a)
the cellular and physiological nature of the EOG response, (b) odor
selection and delivery and (c) application of the EOG in humans,
sh and insect olfaction and pheromonal responsivity [24]. The
trout EOG by amino acids was a monophasic negative voltage
composed of a phasic component which declined to a steady level
[25]. A related report deals with responses to mixtures of amino
acids [26]. Results suggest that when odors are carried by a gentle
wind, the air movement induces EOG oscillations and modulate
synthetic spike patterning of olfactory outputs to the secondary
olfactory relay center [27,28]. Oscillatory potential changes superimposed on the typical EOG were observed in toads during the
breeding season [29]. The potentials were also observed from the
olfactory nerve of the brain. After chemical stimulation of the
human olfactory epithelium, it is possible to record a negative
response in the EOG which is interpreted as the summated receptor
potentials of the olfactory nerve [30]. Data conrm that kinetics of
the cellular processes that underlie the EOG are slowed by Naris
occlusion [31]. The character of changes and maximum decreases of
the EOG amplitude after olfactory nerve axotomy varied in different
parts of the olfactory organ [32].
An article discusses molecular mechanisms of the sense of smell
and taste [33]. Emphasis is on the transformation into electrical
signals. This important contribution, which has received scant
attention, adds credibility to the electrochemical theme. In the
initial process of chemoreception, a stimulatory substance absorbs
onto a membrane. The olfactory cells are primary sensory cells
connected to the end of the olfactory nerve, and they depolarize
when a stimulating substance absorbs in a receptive membrane.
Hence, an impulse is generated directly from the nerve without

involvement of a synapse. The olfactory nerves can be viewed as

information converters for changing chemical information into
electrical signals. Therefore, a large resting potential which is
negative inside the cell is produced. If the nerve is stimulated, the
sodium channel opens and the ions outside ow inside. Opening of
the channel greatly lowers membrane resistance. The potential
change makes the inside more positive. The receptor potential of
the olfactory cell is fundamentally the same as that of the gustatory
cell. The membrane potential change occurs in the presence of
various types of stimulants. When a stimulant is absorbed on the
surface of olfactory cells, the membrane potential changes. There is
a change in the membrane conformation resulting in alteration in
the arrangement of charge transfer complexes and dipoles of the
membranes resulting in change of membrane potential. In living
olfactory cells, membrane resistance is lowered when receptor
potential is generated. Since olfactory cells are part of the olfactory
nerve, the value of membrane resistance should include resistance
at the impulse generating position. The change in membrane
potential is propagated by electrons to the synapse region or
impulse generating position. In a report evaluating function and
disorders of smell, the following comments were made:
.methods are objective which record post-stimulatory electrophysiological events at different steps of olfactory pathways. The
electric response olfactometry representing a cortical evoked socalled twin-potential containing equivalents for the trigeminal
and olfactory sense activity starts to demonstrate its efciency
[34]. An electro-behavioral study was performed of limbic seizures
originating in the olfactory bulb [35].
The above important investigations clearly demonstrate the
participation of bioelectrochemistry in the olfactory process
entailing response to binding with the receptor.
4.2. External electrical stimulus
An appreciable amount of attention has been paid to exposure of
the olfactory system to external electrical stimulus. The results are
in accord with an electrochemical approach to olfactory action.
Electrical stimulation of the human olfactory mucous was performed by means of an electrode [14,36]. The stimulations did not
evoke the sensation of smell, but suppressed smell sensations of
presented odorants. When stimulation followed exposure to an
odorant, the stimulus recalled the faded sensation of the preceding
odorant. Animals were trained to associate the presence of an odor
with the electric shocks [37]. Most adult studies on aversive
learning with Drosophila employed electric shock as a negative
enforcer [38]. The research involved odor-electric shock learning in
the larva and adult. In electric stimulation studies, action potentials
in the olfactory nerve were associated with short-duration, rapidly
depolarizing optical responses in the nerve layer [39]. There are
various other investigations on the electrical stimulus topic
[40e49].
Although the electrical stimulus and the odor molecule both
provide electrochemical force, the stimulus is different in having
mobile electrons as the source. Also, interaction of the external
stimulus with the olfactory nerve is not the same as for the odor
molecule.
5. Part D. cerebral olfactory cortex
Since the brain is replete with electrochemical activity, it is not
surprising that extensive, relevant literature pertains to the olfactory cortex [50]. This part of the cerebrum receives sensory input
from the olfactory bulb. Initially, a G-protein is stimulated which
triggers enzymatic conversion of ATP to cAMP, a second messenger,
followed by activity in membrane channels. The events cause

P. Kovacic / Journal of Electrostatics 70 (2012) 1e6

membrane charge to become more positive, or depolarize, which

travels down the axon of the olfactory receptor cells to the olfactory
nerve. There is considerable literature documenting electrical
effects in the cerebral olfactory cortex. Slices of the guinea pigs
were used to compare the potency of various Ca-channel blockers
on the electrophysiology of synaptic transmission [51]. Listed in
order of potency, the divalent cations of Cd, Ni, Mn, Co and Mg
depressed synaptic transmission. Verapanil and diltiazen
depressed both synaptic transmission and action potential. An
electrophysiological study was made of the degeneration of the
afferent axons of the lateral olfactory tract which gives rise to
excitatory synapses throughout the olfactory cortex of the guinea
pig [52]. Potential changes between the pial and cut surfaces of
slices of guinea pig olfactory cortex produced by gammaaminobutyric acid were recorded with the electrodes [53]. There
are other related reports [54e58].
6. Electron transfer
It is well established that ET processes play important roles in
biology and medicine [59]. The negative electron in motion creates
an electric eld that can interact with others.
Reviews discuss involvement of ET with receptor binding [5,59].
Hence one can imagine participation of ET in the electrochemical
phenomena taking place in the olfactory system. A book also
touches upon the aspect [12]: The [receptor] gap nicely accommodates all molecules (at best those up to 10 wide), and as the
molecule slots into it, suddenly the electrons have before them
a bridge reaching from the in side to the out side, and they hurl
themselves across this bridge. This bridging aspect in receptor,
ligands and ET has been discussed by others [5,59]. ET commonly
occurs in the receptor protein [59]. A report discusses the role
played by EFs, such as those associated with the dipolar peptide
bond. The ions and positive or negative dipoles interact with the
negative electron involved in ET.
7. Cell signaling
Cell signaling (signal transduction) plays an important role in
biology and medicine, in which there is involvement of electrochemical effects [1e9]. Animals, including humans, can be regarded
as complex electrochemical systems which evolved over billions of
years. Organisms interacted with and adapted to an environment of
electrical and magnetic elds. Humans are now immersed in
a man-made atmosphere of such elds whose long-term effects are
unknown. The reviews provide much evidence linking cell
signaling with electrical effects, including ET. There is considerable
literature dealing with electrochemical effects associated with cell
signaling in the olfactory system, providing further support for the
theoretical framework. Investigations of vertebrate signal transduction reveal that calcium-gated chloride channels are activated
during odorant detection in the chemosensory membrane of
olfactory sensory neurons [60]. This activation leads to depolarization of the membrane voltage and can induce electrical excitation. Molecular signaling underlines the response of the olfactory
sensory neurons [61]. A signal transduction cascade leads to
opening of ion channels, generating a current that leads into the
cilia and depolarizes the membrane. Interaction between odorant
and receptor initiates olfactory signal transduction that produces
a cation inux and change in the membrane potential of the
olfactory sensory neuron [62]. Stimulation of the odorant cells
results in a calcium inux that activates the transduction pathway
[63]. Ca acceptors, such as calmodulin, may mediate between the
change in intracellular Ca and the conductance mechanism
underlying the initial electrical event. There are a number of related

studies [64e68]. Evidence for the presence of eNOS in mammalian

olfactory sensory neurons and its involvement in odor adaptation
implicates nitric oxide as an important new element in the olfactory signal transduction [69]. The activating effects of odorants
appear to be mediated via different G-proteins [70]. Thus, at least
two different second messenger pathways seem to be involved in
olfactory signal transduction. Reports address electrochemistry and
cell signaling or signal transduction in connection with various
other items, such as, a review [71] role of proteins and second
messenger [72], G-protein [73], scaffolding proteins [74,75],
proteins and memory [76], olfactory motor gene deletion [77],
cyclic nucleotide-activated channel [78], protein kinase C and
adenylate cyclase [70], second messengers [79], postdocking ligand
behavior [80] and gene effect [81]. There is other pertinent literature [82,83]. A particularly relevant study deals with enhancement
of the cellular olfactory signal by electrical stimulation [84]. Upon
odorant recognition, the electrical cellular activity is enhanced
following each electrical stimulus pulse. Electrical stimulation can
increase the response signal for detecting ligand binding. These
results provide important support for the electrochemical thesis in
relation to receptor binding by odorant and subsequent electrical
activity.
8. Comparison of vibration and electrochemical theories
Generally, odorant molecular rationalized Vibration Theory can
also be accommodated within the electrochemical framework. An
example is the class of molecules with no dipole (see above). In the
following cases, odors are different. Ferrocene and nickelocene
which have similar shapes, possess different chemical properties.
Enantiomers (mirror images) of carvone contain identical functional groups, but different odors. Because of the difference in
stereochemistry, they may bind at different receptors giving rise to
different interactions of the odorant EFs with protein EFs. In
comparison of acetophenone and its deuterated counterpart,
studies have shown different chemical characteristics. In the aldehyde homologous series, the DM values are essentially identical
(Table 2). However, odors of the odds (C7, C9, C11) are waxy,
whereas the evens (C8, C10, C12) are citrus. Spectroscopic studies
show that the aldehydes rotate much more freely in the evens, but
remain conned in the odds [12]. The physical difference might
result in differences in EF interaction between the odd and the even
odorants and receptor proteins. Both thiols (DM 1.60) and
boranes (DM 2.13) have relatively high dipole moments (Table 1).
9. Other aspects
In contrast to other theories, it is evident that a unifying electrochemical thread exists for the various parts of the mechanistic
pathway. However, it is important to recognize that bioactivity is
multifaceted. In the present case, this may involve Shape, Vibration
and Electrochemistry. Usually, the difcult part is assigning relative
importance to the contributors. However, the electrochemical
approach appears to be more comprehensive. In relation to Electrochemistry, future works should determine the validity of this
approach, particularly relative to unanswered questions. There

Table 2
Dipole moments of homologous aldehydes [13].
Aldehyde

Dipole moment (DM)

Acetaldehyde
Propanal
Butanal

2.75
2.52e2.86
2.72

P. Kovacic / Journal of Electrostatics 70 (2012) 1e6

appears to be a similarity to taste in electrochemical mode of action

[33]. In addition to the Shapes and Vibration theories, the electrochemical approach provides a novel perspective. The four parts of
the theory are supported by considerable literature evidence. There
is a unifying framework based on electrochemistry involving dipole
moments, electric elds, receptors, neurons, cerebral olfactory
cortex, cell signaling and electron transfer. There is additional
relevant literature [85e88]. The vibration debate continues [89]
involving both pro [90] and con [91] evidence. Another mechanism, designated the odotope approach, has elements similar to
some aspects of the Electrochemical Theory [89]. Different olfactory receptors have different afnities to specic molecular structural physicochemical properties, and that the differential
activation of these receptors gives rise to a spatiotemporal pattern
of activity that reects the odor.
10. Conclusion
In addition to the Shape and Vibration theories, the electrochemical approach provides a novel perspective. The four parts of
the theory are supported by considerable literature evidence. There
is a unifying thread based on electrochemistry involving dipole
moments, electric elds, receptors, neurons, cerebral olfactory
cortex, cell signaling and electron transfer. There appears to be
a similarity to taste in electrochemical mode of action [92].
Acknowledgments
Editorial assistance by Thelma Chavez, Ashley Berry and Kirstie
Lincoln is acknowledged. The author is grateful to Professor
Andrew Cooksy, SDSU for helpful discussions.
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