DOI:10.1111/j.1600-0625.2006.00529.x
www.blackwellpublishing.com/exd

Review Article

Epidermal keratinocytes as the forefront of the sensory
systemMitsuhiro Denda1, Masashi Nakatani2, Kazuyuki Ikeyama1, Moe Tsutsumi1 and Sumiko Denda1
1

Shiseido Life Science Research Center, Yokohama, Japan;
Graduate School of Information Science and Technology, The University of Tokyo, Tokyo, Japan
Correspondence: Mitsuhiro Denda, PhD, Shiseido Life Science Research Center, 2-12-1, Fukuura, Kanazawa-ku, Yokohama 236-8643, Japan,
Tel.: +81 45 788 7268, Fax: +81 45 788 7277, e-mail: mitsuhiro.denda@to.shiseido.co.jp
2

Accepted for publication 22 November 2006

Abstract Various sensors that respond to physical or chemical
environmental factors have been identified in the peripheral
nervous system. Some of them, which respond to mechanicalstress, osmotic pressure, temperature and chemical stimuli (suchas pH), are also expressed in epidermal keratinocytes.
Neurotransmitters and their receptors, as well as receptors that
regulate the neuroendocrine system of the skin, are also present inkeratinocytes. Thus, broadly speaking, epidermal keratinocytes
appear to be equipped with sensing systems similar to those of theperipheral and central nervous systems. It had long been

considered that only nerve C-terminals in the epidermis play arole in skin surface perception. However, building on earlier workon skin receptors and new findings introduced here, we present inthis review a novel hypothesis of skin sensory perception, i.e. first,
keratinocytes recognize various environmental factors, and thenthe information is processed and conveyed to the nervous system.
Key words: transient receptor potential – P2X – nervous system –neurotransmitter – skin perception

Please cite this paper as: Epidermal keratinocytes as the forefront of the sensory system. Experimental Dermatology 2007; 16: 157–161.

Sensory receptors in keratinocytes
The traditional view of the skin surface sensory system forenvironmental factors, such as temperature, humidity,
mechanical stress and chemical stimuli, has been that the
key sensors are the C fibres, which penetrate into the epidermis (1). However, the terminals of the nerve fibres arequite sparse. For example, the pressure points, which detectmechanical stimuli, are localized at distances of millimetresfrom each other (2). The skin can detect pattern on amuch smaller scale (3–6) than would be expected on thebasis of sampling theory if the nerve terminals were theonly sensors (7). We previously suggested that epidermal
keratinocytes might be at the forefront of skin surface perception (8). This idea has been supported by the recent
cloning of a series of receptors, which are activated by temperature, mechanical stress, osmotic pressure and chemical
stimuli. Many of these receptors are expressed in epidermal
keratinocytes.

Abbreviations: TRP, transient receptor potential; P2X, ATPactivated purinergic receptor; 4a-PDD, 4a-phorbol 12,13didecanone; 2-APB, 2-aminoethoxydiphenyl borate.

One of the most interesting receptor families is called
transient receptor potential (TRP). The TRP receptor
family members have been reported to act as sensors oftemperature or other physical or chemical factors (9), and
TRPV1, TRPV3 and TRPV4 were shown to be present in
epidermal keratinocytes (Fig. 1a) (10–12). TRPV1 seems to
be most strongly expressed in the upper and basal layers of
the epidermis. High expression of the receptor at the surface of the epidermis would be consistent with a role indetecting external temperature. The reason for the highexpression at the basal layer is not clear, but TRPV1 may
also have some role in epidermal–dermal interaction.
TPRV1 is activated by heat (>43C), acidic conditions(pH < 6.6) and capsaicin (13). TRPV3 is activated by heat(>35C), mechanical stress, camphor and 2-aminoethoxydiphenyl borate (2APB) (14,15). TRPV4 is activated byosmotic pressure (9). Previous reports suggest the existenceof a water flux sensor in the epidermis (16,17). TRPV4
might play an important role as a sensor of water flux fromthe skin surface, although it is also activated by heat(>35C) and 4a-phorbol 12,13-didecanone (4a-PDD) (9).
We recently demonstrated that TRPV1 and V4 arestrongly associated with epidermal permeability barrier
homeostasis (18). Activation of TRPV1 by heat (aroundª 2007 The Authors
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Denda et al.

A

B

Figure 1 Immunostaining of human epidermis by anti-TRPV1 serum (a)and anti-P2X3 serum (b). Bars ¼ 50 lm. Both pain receptors are
expressed on keratinocyte cell membrane. TRPV1 is expressed strongly
in the uppermost and basal layers of the epidermis. P2X3 expressedstrongly in the upper area of the epidermis.

43C) or capsaicin after barrier disruption delayed barrier
repair. The delay was blocked by a TRPV1 antagonist, capsazepine. On the other hand, activation of TRPV4 by heat
(36–40C) accelerated barrier repair. These results suggestthat the TRP receptors play an important role in epidermal
homeostasis and indeed may act as temperature sensors
not only for skin, but also for the whole body. Previous
studies indicate that the optimum temperature for barrier
repair (36–40C) (18) is recognized as a pleasant temperature (19). Our emotional and sensory systems seem to‘know’ the appropriate temperature range for skin barrier
homeostasis; this could be related to the fact that dysfunction of barrier homeostasis can be fatal. The roles of the
TRP receptors as components of the sensory system remain
to be fully clarified. However, receptors, such as TRPs,
expressed in the epidermal keratinocytes, which forms theinterface between the environment and the body, could be
expected to play a crucial role in maintaining our internalorgan temperature constant at around 37C under different
environmental conditions. This may be the reason why we
prefer ‘comfortable’ temperature and humidity ranges.
Another interesting receptor family is ATP receptor. The
nervous system contains two distinct families of ATP
receptors (20). One is the ATP-activated purinergic receptor (P2X) family, which is a ligand-gated ion channel, andthe other is the P2Y family of metabotropic, heptahelical
G-protein-coupled receptors. P2X3 was first identified as apain receptor in the peripheral nervous system (21). In thecase of tissue injury or inflammation, ATP is released andactivates P2X3 receptors. We found that P2X3 is expressed158

in human epidermal keratinocytes (Fig. 1b) (22,23), andthe expression was stronger in the upper area of the epidermis. We also showed that P2X3 is produced during terminal differentiation in a keratinocyte culture system (22).
As ATP is released from epidermal keratinocytes by tapestripping or exposure to air (23,24), itching of the skin in
the case of dermatoses (e.g. atopic dermatitis), which arecharacterized by barrier dysfunction or skin surface dryness, might be transduced via the ATP system in the epidermis. TRPV4 might be a sensor of skin dryness, as noted
above (17). Both TRP and ATP receptors on keratinocytes
might play a role in a variety of skin sensations.
Slominski and co-workers found a variety of endocrinological receptors and their agonists in epidermal keratinocytes and melanocytes (25–28). They proposed that the
epidermis and whole skin contain a neuroendocrine system(25), and they suggested an important role of corticotrophin-releasing hormone (CRH) in this system (26). We
have demonstrated that CRH induced ion propagation in
the epidermis (29) and this effect was blocked by an antagonist of the CRH receptor (29). Thus, the endocrinologicalsystem may play an important role in transmitting information from the sensory system of the skin.

Signal transduction
Not only P2X3, but also other P2X and P2Y receptors are
expressed in epidermal keratinocytes (22,30). P2X3 in theepidermal keratinocytes is associated with epidermal barrier
homeostasis (23). Koizumi et al. demonstrated thatmechanical stimulation of a single keratinocyte induced
intracellular calcium elevation not only in that cell, but also
in its neighbours, and this response was prevented byapplication of an ATP receptor blocker (30). They obtained
similar results in a co-culture system of keratinocytes andneurones, and found that mechanical stimulation of a single keratinocyte induced excitation of neurones (30). Thus,
mechanical stress applied to a single keratinocyte can besignalled to surrounding cells and can also evoke excitationof the peripheral nervous system.
Recently, we also demonstrated that air-exposed keratinocytes released ATP, which induced intracellular calcium
propagation in cultured human keratinocytes (24). A
receptor activated by osmotic pressure, such as TRPV4 (9),might be the sensor of air exposure, leading to ATP release.
The diffused ATP might then induce further elevation of
intracellular calcium, and a calcium wave might be
induced. In our study, the propagation of intracellular
calcium was blocked by an ATP receptor blocker (24).
Thus, ATP plays an important role in signal transduction
between keratinocytes, and might also play a crucial role insignal transduction between keratinocytes and the nervous
system.

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Perception of keratinocytes

Purinergic receptors are also related to the function of
TRP receptors. For example, activation of P2Y receptor
reduced the threshold temperature of TRPV1 (31). Suchinteraction between receptors could play a regulatory rolein complex signalling systems. Further study is needed toreach a better understanding of the role of each receptor in
keratinocytes in relation to the skin sensory system.
Not only ATP, but also several neurotransmitters, suchas glutamate and dopamine are secreted from the epidermis
after barrier injury (32,33). The receptors of these transmitters also exist in epidermal keratinocytes (22,23,32,33).
These transmitters might influence not only epidermal
homeostasis, but also the nervous system, as well as theendocrinological and immunological status of the body.
We have recently demonstrated the expression of a functional voltage-gated calcium channel in epidermal keratinocytes (34). The existence of the receptor was previously
suggested by Lee et al. (35), and they also proposed a relationship between the channel and epidermal barrier homeostasis (35). Thus, an electrochemical communication
between adjacent cells (keratinocyte–keratinocyte or keratinocyte–neurone) might play a crucial role in both epidermis–nervous system communication and epidermal
homeostasis. A synapse-like connection between keratinocytes and nerve endings has been identified (36), but nofunctional study was carried out. The normal structure of
the epidermis may be important not only for the permeability barrier, but also for signal transduction. As the otherside of the same coin, abnormality of the epidermis might
affect the sensory system.
The skin neuroendocrine system proposed by Slominski
and co-workers should be important not only for signaltransduction within the skin, but also in skin–nerve andskin–endocrine communication. The operation of the skin–neuroendocrine system has been suggested to be important
for the proper functioning of the immune system, the vascular system, the metabolic system, thermoregulation andthe sensory system (25–28). Further studies of the interaction of keratinocyte sensors, such as TRP and purinergic
receptors, with the endocrine system are needed to understand the role of the epidermis in relation to the whole
body.

Information processing by epidermal
keratinocytes
Epidermal keratinocytes also contain a series of receptors,
which were originally found in the central nervous system
as neurotransmitter receptors. These receptors can be categorized into two groups, i.e. ionotropic receptors andG-protein-coupled receptors. Among the former group, calcium ion or chloride ion permeable channels play a crucialrole in epidermal permeability barrier homeostasis. Topicalapplication of calcium channel agonists delays barrier
recovery, and antagonists accelerate barrier repair(23,32,37). Topical application of chloride ion channel
agonists accelerates the barrier recovery (37,38).
Intracellular cAMP level, which is influenced by G-protein-coupled receptors, plays a crucial role in epidermal
barrier homeostasis (39). Activation of dopamine-2-likereceptors, melatonin receptors and serotonin receptor (type5-HT1) decreases intracellular cAMP, and consequently
accelerates barrier recovery, while activation of adrenergic
b2 receptors increases the intracellular cAMP and delays
barrier repair (40,41). Barrier disruption induces anincrease of intracellular cAMP. Thus, topical application ofagonists of receptors that reduce the intracellular cAMPlevel accelerates barrier repair. The results of our studies
are included in Table 1.
Grando suggested the importance of nicotine type andmuscarine type cholinergic receptors in skin (42), and proposed that the distribution of each receptor is importantfor epidermal homeostasis. We have observed different localizations of dopamine receptors, type 2 and 4 (33). The
role of each receptor might be dependent upon its localization in the epidermis.
We have focused here on the role of these receptors inepidermal barrier homeostasis. However, these receptors
also play crucial roles in the brain. For example, theN-methyl-d-aspartate (NMDA) receptor in the hippocampus
is important for learning and memory (43,44). Conditional
NMDA receptor knockout mice showed a reduced ability
to learn (43), while transgenic mice expressing an increased
level of the receptor showed significantly higher ability tolearn (44). We found NMDA receptor in epidermal

Table 1 Effects of neurotransmitter receptor agonists andantagonists on skin permeability barrier recovery

Ionotropic receptor
P2X receptor (23)NMDA receptor (32)
Cholinergic receptor (Nicotinic) (37)
GABA(A) receptor (38)Glycine receptor (37)
G-protein-coupled receptor
Adrenergic b2 receptor (40)
Dopamine-2-like receptor (33)
Serotonin receptor (41)Melatonin receptor (41)

AcceleratebarrierrecoveryDelaybarrierrecovery

Antagonist
Antagonist
Antagonist
AgonistAgonistAgonistAgonistAgonist–1–

Antagonist
AgonistAgonistAgonistAgonistAntagonist––

1

No effect or no result available.

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Denda et al.

keratinocytes and demonstrated a role of the receptor in
barrier homeostasis and epidermal proliferation (32). It
remains an interesting possibility that the neurotransmitter
receptors in the epidermis also have a much more sophisticated role.
We have reported the presence of several sensory receptors in epidermal keratinocytes as described above(10,11,23). Various environmental factors might be initiallysensed by these receptors, but it is not yet clear whether
signalling occurs from the receptors, and if so, how it ismediated. As we show in Table 1, epidermal keratinocytes
contain most of the representative neurotransmitter receptors originally found in the central nervous system. They
are key components of information processing in the brain.
Thus, we speculate that environmental signals are sensed
by keratinocytes, then processed before being passed to
C-fibres in the epidermis.
As previously noted, human skin can detect patterningat the micron scale (3–6). Recognition of such a pattern
would require processing of information from several keratinocytes. The structures of epidermis and brain are very
different, so the signal processing systems in the two are
not necessarily similar. In this connection, it is interesting
to note that a specific electrochemical information processing system might exist in the epidermis. We have observed
oscillation of intracellular calcium levels in cultured humankeratinocytes (24), with a stable frequency in each keratinocyte. The mechanism and role of the oscillation are not yet
known, but in the absence of extracellular calcium, theoscillation was not observed (24). This might suggest that a
calcium permeable channel contributes to the generation of
the oscillation. Such a stable frequency oscillation cantransfer information, and could play a role in information
processing by epidermal keratinocytes. We are planning toinvestigate this possibility by observing calcium ion propagation in skin slices.
It will also be interesting to examine whether this system
is linked with the various neuropeptides, neurohormones
and their receptors of Slominski et al.’s skin neuroendocrine system (25–28). We may be approaching an understanding of the way in which environmental signals can bedetected, processed and transferred from keratinocytes tothe immune system, physiological system and endocrinological system.

Conclusion
It has been established that epidermal keratinocytes containa variety of sensory and information transmission systems,
and the traditional view of the sensory system in skin,focusing on C-fibres as the sensor, can no longer be regarded as sustainable. Building upon the work of Slominski etal. on the cutaneous neuroendocrine system (25), as well as

160

Figure 2 Schematic illustration of the hypothetical skin surface sensory
system. (a) Traditional view, with C-fibres at the forefront of thesensory system. (b) Proposed new view, with epidermal keratinocytes at
the forefront of the sensory system. A signal is sensed by keratinocytes,
processed and transferred to C-fibre terminals.

our own and other researchers’ findings on keratinocyte receptors, we propose that epidermal keratinocytes are at theforefront of the body’s sensory system, serving to sense avariety of environmental factors (Fig. 2). We suggest thatthe signals generated are processed in the epidermis, andmay influence emotional state, as well as endocrinological,
immunological and physiological status and a variety ofphysiological functions.

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