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Contents lists available at ScienceDirect

Annals of Anatomy
journal homepage: www.elsevier.com/locate/aanat

Molecular basis of dental sensitivity: The odontoblasts are

multisensory cells and express multifunctional ion channels夽
A. Solé-Magdalena a,1 , M. Martínez-Alonso a,1 , C.A. Coronado b , L.M. Junquera c,d , J. Cobo c,e ,
J.A. Vega a,b,∗
a
Departamento de Morfología y Biología Celular Universidad de Oviedo, Spain
b
Facultad de Ciencias de la Salud, Universidad Autónoma de Chile, Temuco, Chile
c
Departamento de Especialidades Médico-Quirúrgicas, Universidad de Oviedo, Spain
d
Servicio de Cirugía Maxilofacial, Hospital Universitario Central de Asturias, Oviedo, Spain
e
Instituto Asturiano de Odontología, Oviedo, Spain

a r t i c l e i n f o a b s t r a c t

Article history: Odontoblasts are the dental pulp cells responsible for the formation of dentin. In addition, accumulating
Received 17 April 2017 data strongly suggest that they can also function as sensory cells that mediate the early steps of mechan-
Received in revised form 22 August 2017 ical, thermic, and chemical dental sensitivity. This assumption is based on the expression of different
Accepted 10 September 2017
families of ion channels involved in various modalities of sensitivity and the release of putative neuro-
transmitters in response to odontoblast stimulation which are able to act on pulp sensory nerve fibers.
Keywords:
This review updates the current knowledge on the expression of transient-potential receptor ion chan-
Odontoblasts
nels and acid-sensing ion channels in odontoblasts, nerve fibers innervating them and trigeminal sensory
Dentin sensitivity
Transient-receptor potential ion channels
neurons, as well as in pulp cells. Moreover, the innervation of the odontoblasts and the interrelationship
Acid-sensing ion channels been odontoblasts and nerve fibers mediated by neurotransmitters was also revisited. These data might
ATP provide the basis for novel therapeutic approaches for the treatment of dentin sensibility and/or dental
ATP receptors pain.
© 2017 Published by Elsevier GmbH.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
2. Innervation of the odontoblasts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
3. Dentin sensitivity and ion channels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
4. The superfamily of transient receptor potential ion channels (TRP) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
5. The superfamily of acid-sensing ion channels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
6. Putative mechanosensors in odontoblasts and trigeminal afferent fibers and neurons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
7. Putative thermosensors in odontoblasts and trigeminal afferent fibers/neurons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
8. Putative chemosensors in odontoblasts and trigeminal afferent fibers and neurons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
9. Other mechano- and thermos-sensitive proteins in odontoblasts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
10. The primary cilium of the odontoblasts and its relation to TRP and ASIC ion channels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
11. Intercellular signal transmission between odontoblasts and nerves . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
12. Future perspectives: TRPs, ASICs, and the ATP signaling system as targets for the treatment of dentin sensitivity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26

夽 This paper belongs to the special issue Dentomaxillary.

∗ Corresponding author at: Departamento de Morfología y Biología Celular, Facultad de Medicina y Ciencias de la Salud, C/Julián Clavería, 6, 33006 Oviedo, Spain.
E-mail addresses: javega@uniovi.es, javega@hotmail.es (J.A. Vega).
1
These authors contributed equally to this paper.

https://doi.org/10.1016/j.aanat.2017.09.006
0940-9602/© 2017 Published by Elsevier GmbH.
 A. Solé-Magdalena et al. / Annals of Anatomy 215 (2018) 20–29 21

1. Introduction presence of ion channels, primarily belonging to the TRP and ASICs
superfamilies, in these cells. The blockade of these channels would
Odontoblasts are specialized cells of the dental pulp originating provide a novel therapeutic intervention for the treatment of dentin
from the neural crest (Mayor and Theveneau, 2013) which migrate sensitivity and tooth pain (see El Karim et al., 2011; Alexander et al.,
beneath the oral epithelium and finally differentiate into cells that 2013; Kweon and Suh, 2013; Holzer and Izzo, 2014; Kaneko and
will organize and regulate the synthesis of the mineralized dentin Szallasi, 2014; Nilius and Szallasi, 2014; Sousa-Valente et al., 2014;
matrix (Arana-Chavez and Massa, 2004; Bleicher, 2014; Kawashima Baron and Lingueglia, 2015).
and Okiji, 2016). During maturation, odontoblasts exhibit change in
gene expression, acquiring a typical morphology with a body and a
2. Innervation of the odontoblasts
long process (Simon et al., 2009; Byers and Westenbroek, 2011). The
cell bodies of the odontoblasts are located at the dentin-pulp inter-
Nerves entering the dental pulp consist of sensory and post-
face complex where they are organized in a palisade between the
ganglionic sympathetic fibres arising from the trigeminal and the
mineralized tissues (enamel and dentin) and the living tissue (the
superior sympathetic ganglia neurons, respectively. Within the
pulp) of the tooth. In fact, odontoblasts are connected at their api-
dental pulp they innervate the blood vessels, the pulp cells, and the
cal pole (i.e. the zones connecting the bodies with the processes) by
odontoblasts through fibers evolved from the so-called subodon-
numerous junctional complexes (tight junctions and desmosome-
toblastic plexus (Raschkow’s plexus; Fig. 2). Odontoblasts, both at
like) forming a selective barrier controlling the relationship and
the dentin-pulp border and within the dentinal tubules, are inner-
trafficking between dentin and pulp and vice versa under physio-
vated by a dense network of myelinated A␦ and unmyelinated C
logical and pathological conditions. The odontoblast processes are
sensory nerve fibers. However, the definitive structure of the con-
contained in dentinal tubules bathing in the dentinal fluid (Fig. 1;
tacts between the odontoblasts and the subodontoblastic plexus
see Murray et al., 2003; Bleicher, 2014).
remains to be elucidated (see Allard et al., 2006). The A␦ fibers are
In addition to the formation of the dentin, the odontoblasts pre-
principally located at the pulp-dentin border and reach the basal
sumably mediate the early stage of sensory processes, playing a key
odontoblast layer, while the C fibers enter the dentin tubules (Byers
role in mechanical, thermal, and chemical sensation, thus, in dental
and Närhi, 1999; Struys et al., 2007). Byers (1984) observed that
sensitivity and pain (Gillam, 1995; Maurin et al., 2003). Because of
more than 40% of the dentinal tubules contain nerve fibres and
their location in the tooth, odontoblasts are the first targets of exter-
many of them more than one. An elegant and detailed study car-
nal stimuli (chemicals changes in dentinal fluid, thermal variations
ried out by Cardá and Peydró (2006) in human teeth demonstrated
or mechanical forces), and can therefore act as sensory cells for the
that about 30–70% of odontoblast processes are in contact with
detection of these sensory signals. Dentin sensitivity is due to the
nerve endings that enter the innermost segments of the dentinal
direct exposure of dentin to mechanical, chemical and/or thermal
tubules, no further than 200 ␮m from the pulp. They also observed
stimuli. In this way, the odontoblasts express mechanosensitive,
that each dentinal tubule contains a single nerve fiber which varies
chemosensitive and thermosensitive transient receptor potential
in relationship to the odontoblast process from simple adjacency
(TRP; Magloire et al., 2010) and acid-sensing (ASIC; Solé-Magdalena
to encircling. Nevertheless, no synapse-like structures have been
et al., 2011) ion channels, which are regarded as necessary to ini-
observed (Byers et al., 1987; Ibuki et al., 1996; Cardá and Peydró,
tiate those sensory processes (Delmas and Coste, 2013; Nilius and
2006).
Szallasi, 2014; Ranade et al., 2015; Sharif-Naeini, 2015). Further-
The pulp is a highly vascular tissue with a dense capillary plexus
more, it has been demonstrated that gating ion channels present in
under the odontoblast layer that is innervated by postganglionic
odontoblasts induce release of ATP, which is the primary transmit-
sympathetic nerve fibers (Yoshida and Ohshima, 1996).
ter between odontoblasts and nerve fibers (Egbuniwe et al., 2014;
The pattern of innervation of odontoblasts is directly regu-
Liu et al., 2015; Lee et al., 2017) thus initiating the transmission of
lated by local nerve attractive and nerve repulsive molecules (such
a given sensory modality to the central nervous system.
as nerve growth factor, glial-cell line derived neutrophic factor,
This review is an update of the molecular basis of mechano-
sema7A, or reelin) released from the pulp cells and the odonto-
, chemical- and thermo-sensitivity in odontoblasts, based on the

Fig. 2. Double immunofluorecence showing the innervation (green fluorescence)

Fig. 1. (A) Schematic representation of the odontoblasts and their relations to
the dentin and nerve fibers. Pictures show dontoblasts immunolabelled with anti-
vimentin (B), anti-TRPV4 (C) and anti-PGP 9.5 antibodies (D). Vimentin and PGP
9.5 are an intermediate cytoskeletal protein and a cytosolic protein, respectively,
present in the odontoblasts and their processes. TRPV4 is an ion channel detected
in the odontoblasts and related to different modalities of sensitivity. d: dentin; O:
odontoblasts; p: pulp.
of human odontoblasts (red fluorescence). The odontoblasts were immunolabelled
for detection of vimentin which was found in both the cell bodies and processes.
Spots of green fluorescence (arrows) indicate axons immunolabelled for detection
of neurofilaments proteins (NFP). NFP-positive nerve profiles contact odontoblast
cell bodies and also enter the deep segment of dentinal canals. Objective 60×/1.25
oil; pinhole airy 1, XY resolution 156 nm and Z resolution 334 nm. (For interpretation
of the references to colour in this figure legend, the reader is referred to the web
version of this article.)
22 A. Solé-Magdalena et al. / Annals of Anatomy 215 (2018) 20–29
blasts themselves; these molecules direct the nerve terminals to
appropriate sites (Mitsiadis and Luukko, 1995; Luukko et al., 1997;
Maurin et al., 2004, 2005). For example, nerve growth factor and
its high affinity signaling receptor TrkA regulate the development,
density and maintenance of both nociceptive and postganglionic
nerve fibers (Kirstein and Fariñas, 2002). Consistently, the den-
tal pulp of TrkA-deficient mice lack nerve fibers in tooth pulp,
including sympathetic fibers, calcitonin gene-related peptide and
substance P nociceptive fibers (Matsuo et al., 2001; Ichikawa et al.,
2004).
3. Dentin sensitivity and ion channels
The dentin sensitivity is caused by its exposition to mechanical,
chemical or thermal stimuli. When enamel is removed or injured,
and the dentin tubules opened, the liquid content of the dentinal
tubules, the odontoblasts, the trigeminal nerve entering the tooth,
and probably also the dental pulp cells, are exposed to the sensi-
tivizing agents. Thus, dentin sensitivity results from the activation
of dental (i.e., trigeminal) sensory neurons for various mechani-
cal, thermic or chemical stimuli which affect the dentinal fluid, the
dentinal tubule content (nerves and odontoblast processes) or the
dental pulp cells. Nevertheless, the molecular mechanisms under-
lying tooth-dentin sensitivity have not been fully elucidated.
Three hypotheses are currently considered to explain dentinal
sensitivity. The first hypothesis (nerve theory; Fig. 3a) is based
on the direct stimulation of dental nerves and the properties
of trigeminal primary afferents innervating the tooth, especially
the functional expression of mechanosensitive, chemosensitive
or thermosensitive ion channels. The second hypothesis (hydro-
dynamic theory; Fig. 3b) attributes dentinal sensitivity to nerve
stimulation by fluid movement within dentinal tubules: cold stimu-
lation causes an outward fluid flow while a hot stimulation induces
an inward fluid flow in dentinal tubules (Linsuwanont et al., 2007).
Moreover, the pulp cells and nerves can also detect the tempera-
ture and chemical composition of the fluid (Andrew and Matthews,
2002). The third hypothesis (odontoblastic theory; Fig. 3c) is consis-
tent with the capability of the odontoblasts to sense diverse stimuli.
The presence in these cells of specific ion channels strongly sug-
gest that they are able to detect mechanical, chemical, and thermal
signals (Chung and Oh, 2013; Chung et al., 2013).
These three theories are not mutually exclusive and cannot
be considered separately because of the presence of nerves and
odontoblast processes within the dentinal tubules, bathing in the
dentinal fluid, and the close apposition of the odontoblasts to the
dentinal or basal nerves terminals. Thus, external stimuli modify-
ing the dentinal fluid induce responses in the odontoblasts, in the
nerves, and in the odontoblast–nerve complex, and this may rep-
resent a unique polymodal sensory system responsible for dentin
sensibility. In this context the odontoblasts play a pivotal role in sig-
nal transduction, but how they sense signals and how these signals
are transmitted to axons are questions which have been resolved
in part only recently.
Various studies in non-vertebrates and vertebrates have iden-
tified several ion channels that are responsible, or are required,
for detecting a range of thermal, chemical or mechanical stimuli,
and stimuli-transduction ion channels are known for most sensory
modalities (Belmonte and Viana, 2008; Damann et al., 2008; Nilius
and Szallasi, 2014; Jardín et al., 2017).
The identification of ion channels selectively activated by differ-
ent stimuli, supported the concept that the specificity of a sensory
cell is determined by their expression of a particular ion channel
conferring its selectivity to respond to a unique stimulus. Never-
theless, it is currently accepted that the ion channels proposed as
specific transducers are not as neatly and selectively associated
with the distinct types of sensibility. In fact, ion channels originally
associated with the transduction of one particular form of energy
are also activated by different stimuli. In addition, some ion chan-
nels associated with a specific type of stimulus are expressed in
sensory cells functionally defined as specific for other sensitivities.
In other words, a specific ion channel can be expressed in more than
a sensory cell type, and each cell type may express more than one
type of ion channel. Thus, the capacity exhibited by the different
functional types of sensory cells, to preferentially detect a specific
stimulus is the result of a characteristic combinatorial expression of
different ion channels (Liedtke, 2007; Belmonte and Viana, 2008;
Ezak et al., 2010); and this is the case for the trigeminal neurons
(Vandewauw et al., 2013) and the odontoblasts (Magloire et al.,
2010).
Several classes of ion channels have been identified in odon-
toblasts which are involved in nociception and other types of
sensitivity, such as L-type Ca2+ channels, mechanosensitive K+
channels and voltage-gated Na+ channels (Guo and Davidson, 1998;
Magloire et al., 2003, 2009, 2010; Allard et al., 2000, 2006; Solé-
Magdalena et al., 2011; Ichikawa et al., 2012). Here we focused
on two superfamilies of ion channels: TRP ion channels and
degenerin/epithelial Na+ channels (DEG/ENa+ C), particularly ASICs.
4. The superfamily of transient receptor potential ion
channels (TRP)
TRPs are integral membrane proteins that function as ion chan-
nels. They are non-selective cation channels, a few are highly
Ca2+ selective and some are permeable for highly hydrated Mg2+ .
The TRP superfamily is subdivided into seven subfamilies: TRPC
(canonical), TRPV (vanilloid), TRPM (melastatin), TRPP (polycystin),
TRPML (mucolipin), TRPA (ankyrin) and TRPN (NOMPC-like); the
latter being found only in invertebrates and fishes. At least 28 dif-
ferent TRP proteins have been identified in mammals. Structurally,
a typical TRP protein contains six putative transmembrane domains
(S1 to S6) with a pore-forming reentrant loop between S5 and
S6. Intracellular N- and C-termini are variable in length and con-
sist of a variety of domains (Clapham et al., 2005; Hellmich and
Gaudet, 2014; Nilius and Szallasi, 2014). This ion channel superfam-
ily shows a variety of gating mechanisms with modes of activation
ranging from ligand binding, voltage and changes in temperature to
covalent modifications of nucleophilic residues (see for a review Eid
and Cortright, 2009; Nilius and Owsianik, 2011; Nilius and Szallasi,
2014).
5. The superfamily of acid-sensing ion channels
ASICs are Na+ -selective cation channels which are voltage-
insensitive and amiloride-sensitive and monitor moderate devia-
tions from the physiological values of extracellular pH (Waldmann
et al., 1997; Lingueglia, 2007; Lumpkin and Caterina, 2007; Baron
and Lingueglia, 2015). Six ASIC proteins encoded by four genes have
been identified: ASIC1a, ASIC1b, ASIC2a, ASIC2b, ASIC3, and ASIC4
which differ in their kinetics, external pH sensitivity, tissue dis-
tribution and pharmacological properties (Krishtal, 2003). The pH
values required for half-maximal activation are 6.2–6.8 for ASIC1a,
5.9–6.2 for ASIC1b, 4.9 for ASIC2a and 6.5–6.7 for ASIC3 (Kress
and Waldmann, 2006; Hanukoglu, 2017). In addition, some ASICs
may work as mechanosensors (or are required for mechanosen-
sation) and nociception (Wemmie et al., 2006; Holzer, 2009, 2011;
Sherwood et al., 2012; Zha, 2013; Holzer and Izzo, 2014; Omerbašić
et al., 2015). Structurally, ASICs consist of two transmembrane
domains and a large extracellular loop (Sherwood et al., 2012).
The members of these two families of ion channels exhibiting
mechanosensitivity, thermosensitivity and chemosensitivity are
 A. Solé-Magdalena et al. / Annals of Anatomy 215 (2018) 20–29
Fig. 3. Schematic representation of the three main theories explaining the dentin sensitivity. The nerve theory postulates the direct stimulation of dentinal tubules and pulpar nerve terminals; the hydrodynamic theory assumes
stimulation of dental nerves by dentinal fluid; and the odontoblastic theory postulates direct stimulation of odontoblast, and is based on the expression of several ion channels by these cells.

23
24 A. Solé-Magdalena et al. / Annals of Anatomy 215 (2018) 20–29
Table 1
Members of the TRP and Deg/ENaC superfamilies exhibiting mechano-, thermo- and
chemo-sensitivity (based on Belmonte and Viana, 2008).
Mechanosensing Thermosensing Chemiosensing
TRPC1
PRPC6
TRPV1 TRPV1 TRPV1
TRPV2 TRPV2
TRPV3
TRPV4 TRPV4
TRPM3
TRPM4
TRPM8 TRPM8
TRPA1 TRPA1
TRPP2
ASIC 1 ASIC1 ASIC1
ASIC2 ASIC2 ASIC2
ASIC3 ASIC3 ASIC3
summarized in Table 1. In the following pages the occurrence of
these ion channels in the odontoblast and the nerve fibres supply-
ing them will be detailed. Regarding the trigeminal neurons, almost
all the ion channels involved in all sensory modalities have been
detected in these cells. In fact, in the murine trigeminal neurons 17
of the 28 TRP channel genes were detectable (TRPA1, TRPC1, TRPC3,
TRPC4, TRPC5, TRPM2, TRPM3, TRPM4, TRPM5, TRPM6, TRPM7,
TRPM8, TRPV1, TRPV2, TRPV4, TRPML1 and TRPP2; Vandewauw
et al., 2013), while in the human trigeminal ganglion 10 TRPs
(TRPC1, TRPM2, TRPM3, TRPM7, TRPM8, TRPV1, TRPV2, TRPV3,
TRPV4 and TRPML1) and ASIC1-3 have been identified (Flegel et al.,
2015; Fu et al., 2016).
6. Putative mechanosensors in odontoblasts and
trigeminal afferent fibers and neurons
To understand what mechanoproteins are, it is necessary to have
in mind that they are not receptors and that mechanical forces
are not ligands. The force is rather an “anti-ligand” because it can
disrupt intramolecular or intermolecular interactions to trigger a
conformational transmission (see Sukharev and Anishkin, 2004).
Most of the ion channels candidates for mechanosensors belong
to the superfamilies of DEG/ENaC and TRP ion channels (see for
a review Gillespie and Walker, 2001; Lumpkin and Caterina, 2007;
Arnadottir and Chalfie, 2010; Delmas and Coste, 2013; Ranade et al.,
2015). Moreover, members of the two potassium pore (K2P ) chan-
nels and the product of Piezo1 and Piezo2 genes have been also
identified as components of mechanically activated cation channels
(Coste et al., 2010; Delmas and Coste, 2013; Ranade et al., 2015).
The putative mechanosensors TRPV4, TRPM3, TRPP1 and TRPP2
are expressed in cultured mouse odontoblasts (Son et al., 2009; Sato
et al., 2013), whereas the adult rat odontoblasts express TRPM7,
TRPC1, TRPC6, and TRPV4 (Kwon et al., 2014), and human odonto-
blasts display immunoreactivity for TRPV4, ASIC2 and the ␤- and
ϒ-ENaC, but not ␣-ENaC, subunits (Solé-Magdalena et al., 2011).
TRPP1 and TRPP2, which act together as a mechanical receptor, are
present at the surface of odontoblasts, and appear to be located at
the base of the primary cilium (Thivichon-Prince et al., 2009).
TRPM3, TRPV4, TRPA1, ASIC3, ENaC-␣ and ENaC-ϒ ion chan-
nels have been detected in primary afferent dental neurons
(Hermanstyne et al., 2008; Vandewauw et al., 2013).
7. Putative thermosensors in odontoblasts and trigeminal
afferent fibers/neurons
Six members of the TRP superfamily, TRPA1, TRPM8, TRPV1,
TRPV2, TRPV3, and TRPV4, proposed to participate in thermosen-
sation have been detected in sensory nerves, but only some of
them have been detected in the odontoblasts or trigeminal affer-
ent neurons. TRPV1, TRPV2, TRPV3, and TRPV4 have incompletely
overlapping functions over a broad thermal range from warm to
hot. While TRPA1 and TRPM8 respond to cool and cold, TRPV1 and
TRPV2 are activated by painful levels of heat (>43 ◦ C and >52 ◦ C,
respectively), TRPV3 and TRPV4 respond to non-painful warmth
(33–39 ◦ C), TRPM 8 is activated by non-painful cool temperatures
(<25 ◦ C), and TRPA 1 is activated by painful cold (<18 ◦ C; Palkar
et al., 2015). TRPV1 is also responsive to noxious stimuli and vari-
ous chemical agents (Reid, 2005; Nieto-Posadas et al., 2011; Wetsel,
2011; Vay et al., 2012; Voets, 2012).
Heat- and cold-sensing TRP channels, TRPV1, TRPV2, and TRPV3,
TRPM8 and TRPA1 are functionally expressed in odontoblasts (Son
et al., 2009; El Karim et al., 2011; Kim et al., 2012; Sato et al., 2013),
but the results vary widely among species. Cultured mouse odonto-
blastic cells express TRPV1, TRPV2, TRPV3, TRPV4, and TRPM3, but
not TRPM8 and TRPA1 (Son et al., 2009), while odontoblasts from
adults rats express TRPA1 (Byers and Westenbroek, 2011) and lack
TRPV1 or TRPV2 (Yeon et al., 2009). In partial disagreement with
these findings, Tsumura et al. (2012, 2013) have detected functional
expression of TRPV1, TRPM8 and TRPA1 channels in rat odonto-
blasts. The human odontoblasts contain TRPM8, TRPA1 along with
TRPV1 (Okumura et al., 2005; El Karim et al., 2011; Tazawa et al.,
2017). Finally, in human immortalized dental pulp cells derived
from an odontoblast phenotype, Egbuniwe et al. (2014) demon-
strated expression of mRNA for TRPA1, TRPV1, and TRPV4 but not
TRPM8. Nevertheless, although all these putative thermal sensors
are present in odontoblasts, it is unlikely that these cells serve as
thermal sensors (Yeon et al., 2009).
TRPV1, TRPV2 and TRPA1 are also expressed in dental affer-
ents whereas primary afferent trigeminal neurons express TRPV1,
TRPV4, TRPA1, TRPM8 and TRPM3 (Story et al., 2003; Park et al.,
2006; Chung et al., 2013). In the human dental pulp, TRPA1 was
expressed in a large number of axons branching in the peripheral
pulp as well as in the cell body of odontoblasts (Kim et al., 2012).
8. Putative chemosensors in odontoblasts and trigeminal
afferent fibers and neurons
The chemosensory capacity of the sensory systems relies on the
appropriate expression of chemoreceptors, which detect chemical
stimuli and transduce sensory information into cellular signals. The
molecular mechanism of chemosensation in the trigeminal system
has been revised recently by Viana (2010), but without any direct
reference to the dental sensitivity.
Most of the authors suggest that chemosensation is determined
primarily by the chemical activation of nociceptors and thermore-
ceptors, and that activation by chemicals involves the direct activity
of an ion channel by chemical stimuli: the so-called ionotrophic
transduction (Wood and Docherty, 1997; Lee et al., 2005). The
ionotropic channels include some TRPs, ASICs and two-pore K2 P
channels in trigeminal neurons (Caterina et al., 1997; Tominaga
and Tominaga, 2005; Bautista and Julius, 2008; Viana, 2010; Flegel
et al., 2015), and at least TRPM5 in the odontoblasts (Khatibi Shahidi
et al., 2015).
The data about the presence of primary TRP and ASIC ion
channels involved in mechanosensitivity and thermosensitivity
in odontoblasts, pulpar nerve fibres and trigeminal neurons are
summarized in Fig. 4. Moreover, Fig. 5 show pictures of human
odontoblasts showing immunoreactivity for some ion channels
mentioned in this review.
 A. Solé-Magdalena et al. / Annals of Anatomy 215 (2018) 20–29
Fig. 4. Schematic representation of the distribution of TRP and ASIC ion channels in
odontoblasts, dental nerve fibres and trigeminal ganglia neurons.
9. Other mechano- and thermos-sensitive proteins in
odontoblasts
In addition to the above mentioned TRP and ASIC ion channels,
members of the two-pore domain potassium (K2p ) channels fam-
ily, and the product of Piezo1 and Piezo2 genes are also considered
as putative mechanotransducer channels (Lumpkin and Caterina,
2007; Coste et al., 2010; Lumpkin et al., 2010; Ranade et al., 2015;
Sharif-Naeini, 2015).
K2P ion channels consist of six subfamilies within the super-
family of K+ -selective channel subunits (Yost, 2003; Sabbadinia
and Yost, 2009), and two members of this superfamily, TREK1 and
TRAAK, are among the few channels for which a direct mechanical
gating has been demonstrated (Maingret et al., 2000). TREK/TRAAK
channels are co-expressed with TRP-thermo channels, and can also
work as nociceptors, thermosensors and controlling pain produced
by mechanical stimulation (Maingret et al., 1999a, 1999b, 2000;
Chemin et al., 2005; Alloui et al., 2006; Noël et al., 2009). Inter-
estingly, TREK1 and TREK2 are present in neurons innervating the
dental pulp (Hermanstyne et al., 2008), and the transcripts of TREK1
are expressed in the human odontoblasts (Magloire et al., 2003).
On the other hand, it has been demonstrated that the products
of Piezo1 and Piezo2 genes are rapidly adapting, mechanically acti-
vated ion channels (Ranade et al., 2014; Volkers et al., 2015). Piezo2
has been reported in trigeminal neurons innervating tissues other
Fig. 5. Immunohistochemical localization of some TRP and ASIC1 ion channels in human odontoblasts. Positive immunostaining was detected in both the cell bodies and
processes. d: dentin; o: odontoblasts; p: pulp.
25
than dental pulp (Bron et al., 2014) and, recently, Khatibi Shahidi
et al. (2015) found occurrence of Piezo2 in murine odontoblasts.
10. The primary cilium of the odontoblasts and its relation
to TRP and ASIC ion channels
Typically, the odontoblasts contain a primary cilium than is
involved in odontogenesis (Thivichon-Prince et al., 2009), but also
in detection of fluid movement in dentinal tissue (elicited by high
pressure, osmotic, chemical or thermal stimuli) that may cause a
cilium deformation thus initiating a signal transduction pathway
(Magloire et al., 2004). The primary cilium is a cell system which
senses and transduces mechanical and chemical stimuli (Pazour
and Witman, 2003; Praetorius and Spring, 2005; Muhammad et al.,
2012; Prasad et al., 2014). Both processes involve Ca2+ entry and
require the presence of stretch-activated Ca2+ channels (poly-
cystins) localized in the cilia (Delmas, 2004; Delmas et al., 2004;
Praetorius and Spring, 2005). It is also noteworthy that the mem-
brane of the cilium contains multiple channel proteins, including
a variety of Ca2+ -ion permeable channels that play a role in Ca2+ -
mediated fluid-flow mechanosensation (Anishkin and Kung, 2013;
Delling et al., 2013). Very probably, ASICs, which have been local-
ized in the cilia of various tissues, are among these ion channels
(Kikuchi et al., 2008; Kikuchi et al., 2010; Viña et al., 2015), as
well TRP channels, since the cilium is a unique Ca2+ compart-
ment regulated by a heteromeric TRP channel (Giamarchi et al.,
2006; Delling et al., 2013). On the other hand, the mechanosen-
sory and chemosensory functions of the cilium are those of ASIC2
(see Sherwood et al., 2012), thus it can be speculated that ASIC2
participates in the ciliary function.
11. Intercellular signal transmission between odontoblasts
and nerves
How is the firing of odontoblasts transmitted to nerve endings
supplying them? As previously mentioned, no specific synaptic-like
structures have been observed between nerve fibers and odonto-
blasts even when they are in close proximity (Byers, 1984; Cardá
and Peydró, 2006). Nevertheless, release of mediators from stim-
ulated odontoblasts into the gap-space between odontoblasts and
nerves, followed by signaling to dental afferents, are sine qua non
26 A. Solé-Magdalena et al. / Annals of Anatomy 215 (2018) 20–29
Fig. 6. Schematic representation of the molecular mechanisms coupling direct
odontoblast stimulation or activation of odontoblastic TRP/ASIC ion channels that
results in ATP outflow. The extracellular ATP binds to specific receptors present in
nerve fibers, odontoblasts and other pulp cells acting via synaptic-like (grey lines),
autocrine (red line) or paracrine (blue line) mechanisms. (For interpretation of the
references to colour in this figure legend, the reader is referred to the web version
of this article.)
conditions supporting the hypothesis that odontoblasts are sensory
cells, and, thus, the odontogenic theory of dentin sensitivity.
Among the proposed mediators are nitric oxide (Korkmaz et al.,
2005), galanin (Suzuki et al., 2002), glutamate (Nishiyama et al.,
2016) and, especially, extracellular purines such as ATP and adeno-
sine (see for a review Lim and Mitchel, 2012; Lee et al., 2017);
the process of signaling throughout purines is known as puriner-
gic transmission. Thus, purinergic signaling refers to the process
by which purines and pyrimidines mediate cellular responses fol-
lowing stimulation of specific receptors. Every cell has a supply of
cytoplasmic ATP that can be released under physiological condi-
tions through fusion of ATP-containing vesicles with the plasma
membrane in a classic release pathway. Also, ATP can passively
efflux out of the cell through permeant membrane pores or chan-
nels (anion channels, connexin and pannexin hemichannels), or via
a hybrid mechanism throughout Ca2+ -dependent fusion of vesi-
cles containing permeant channels with the plasma membrane
(Reigada and Mitchell, 2005). Odontoblasts expressed the gap
junction protein connexin43, or pannexin-1 which can form trans-
membrane hemichannels for ATP release (Liu et al., 2012; Fig. 6).
Multiple release mechanisms may exist within the same cell
able to be activated by different stimuli, although ATP-release is fre-
quently triggered by mechanical stimuli (Xia et al., 2012). Released
ATP acts over specific receptors and is then rapidly dephosphory-
lated by a series of extracellular enzymes converting ATP directly
into AMP and pyrophosphate (Goding et al., 2003; Zimmermann,
2006).
The purinergic receptors fall into two main categories termed P1
and P2 receptors (Burnstock, 1978). P1 are receptors for adenosine,
and P2 receptors for ATP. P1 receptors are G protein-coupled recep-
tors. P2 receptors are subclassified into ionotropic cation channels
P2X receptors and G-protein-coupled P2Y receptors. To date, seven
P2X receptors (P2 × 1R-7R) and eight P2Y receptors (P2Y1R, P2Y2R,
P2Y4R, P2Y6R, P2Y11R, P2Y12R, P2Y13R and P2Y14R) have been
identified in mammals (Burnstock, 2006, 2006; Coddou et al., 2011;
von Kugelgen and Harden, 2011).
The P2X receptors, differ in their rates of inactivation and sen-
sitivity to ATP, the P2 × 7R requiring the highest concentrations
of ATP for activation and inactivating most slowly (North, 2002).
P2XRs are expressed in the nociceptive trigeminal ganglion cells
(Staikopoulos et al., 2007; Kim et al., 2008) as well as in the dental
pulp cells (Alavi et al., 2001; Renton et al., 2003; Wang et al., 2016).
Moreover, myelinated and unmyelinated P2X positive nerve fibers
were detected in the subodontoblastic plexus in close association
with odontoblasts (Cook et al., 1997; Alavi et al., 2001; Sharma and
Pradeep, 2006). In rats, P2XR2 and P2XR3 receptors were found
in both pulp nerves and a subpopulation of trigeminal ganglion
neurons (Matsuka et al., 2001; Jiang and Gu, 2002; Staikopoulos
et al., 2007; Chung et al., 2008; Kuroda et al., 2012). Furthermore,
odontoblast themselves express several P2XRs of different sub-
types (Lee et al., 2017; Shiozaki et al., 2017) thus suggesting that
ATP might regulate the physiology of the odontoblasts throughout
autocrine–paracrine mechanisms, since inhibition of interodonto-
blastic communication can be reached blocking of ATP release (Lee
et al., 2017). Furthermore, P2Y receptor subtypes are present in
pulp cells (Wang et al., 2016), trigeminal neurons (Li et al., 2014;
Kawaguchi et al., 2015) and trigeminal satellite glial cells (Magni
et al., 2015), as well as in odontoblasts (Sato et al., 2015; Wang
et al., 2016).
It has been traditionally accepted that mechanical distortion or
direct stimulation of the odontoblasts lead to ATP release, presum-
ably acting via ion channels. The activation of TRPA1 and TRPV4,
but not TRPV1, in human odontoblast-like cells causes an increase
in ATP release than can be abolished by selective TRP antagonists
(Egbuniwe et al., 2014). Also, following mechanical stimuli activ-
ity of TRPV1, TRPV3, TRPV4 and TRPA1, but not TRPM8, there is
a release of ATP via pannexina-1 that transmits a signal to P2X3
receptors of trigeminal neurons (Shibukawa et al., 2013, 2015; Sato
et al., 2015; Fig. 6).
12. Future perspectives: TRPs, ASICs, and the ATP signaling
system as targets for the treatment of dentin sensitivity
The expression of mechanosensing, thermosensing and
chemosensing ion channels by odontoblasts; the close relation-
ships between odontoblasts and nerve fibers; the release of ATP by
the odontoblasts in response to, at least, mechanical stimulation;
the existence of an enzymatic apparatus for ATP degradation
in dental pulp; and the expression of ATP receptors in dental
afferents, strongly suggests that ATP might act as a signaling
molecule between odontoblasts and neurons in the sensory
transduction sequence for dentinal sensibility (Lim and Mitchell,
2012; Shibukawa et al., 2015). Taken together, these steps in the
transmission of signals demonstrate the key role of odontoblasts as
sensory cells, lending support to the odontoblastic theory of dentin
sensitivity (Fig. 6). Consistenty, the disruption of these sequential
events using appropriate pharmacological modulators for TRP and
ASIC ion channels (El Karim et al., 2011; Alexander et al., 2013) or
prurinergic transmission (Burnstock, 2006, 2009) would provide a
novel therapeutic approach in the treatment of dentin sensitivity.
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