Vous êtes sur la page 1sur 11

Pflugers Arch - Eur J Physiol (2015) 467:109119

DOI 10.1007/s00424-014-1651-7

INVITED REVIEW

Transduction and encoding sensory information


by skin mechanoreceptors
Jizhe Hao & Caroline Bonnet & Muriel Amsalem &
Jrme Ruel & Patrick Delmas

Received: 31 October 2014 / Revised: 6 November 2014 / Accepted: 7 November 2014 / Published online: 23 November 2014
# Springer-Verlag Berlin Heidelberg 2014

Abstract Physical contact with the external world occurs inform us about objects in our external environment through
through specialized neural structures called mechanoreceptors. touch and pain and about the movement of our body parts
Cutaneous mechanoreceptors provide information to the central through the stimulation of muscle and joints. Although all sets
nervous system (CNS) about touch, pressure, vibration, and skin of mechanoreceptors are excited by indentation of the skin, they
stretch. The physiological function of these mechanoreceptors is signal different types of information from a light brush to
to convert physical forces into neuronal signals. Key questions noxious stimuli (reviewed in [1, 5, 22, 23, 56, 57, 88]). Cuta-
concern the molecular identity of the mechanoelectric transducer neous mechanoreceptors convey four basic types of informa-
channels and the mechanisms by which the physical parameters tion when stimulatedmodality (e.g., gentle touch, vibration,
of the mechanical stimulus are encoded into patterns of action stretch, injurious forces), location, intensity, and timing [1, 23,
potentials (APs). Compelling data indicate that the biophysical 31, 81]. At the receptive site, mechanical energy is transduced
traits of mechanosensitive channels combined with the collec- into a change in membrane potential that is called receptor
tion of voltage-gated channels are essential to describe the nature potential. The receptor potential is then transformed into a
of the stimulus. Recent research also points to a critical role of neural pulse code, in which the frequency of action potentials
the auxiliary cell-nerve ending communication in encoding (APs) reflects to some extent the amplitude of the receptor
stimulus properties. This review describes the characteristics of potential. Strong stimuli evoke larger receptor potentials, which
ion channels responsible for translating mechanical stimuli into generate a higher frequency of APs. Mechanoreceptor firing
the neural codes that underlie touch perception and pain. may fade out over time when confronted with a steady stimulus,
which accounts for the perceptual adaptation in which the
stimulus vanishes from consciousness.
Keywords Mechanosensation . Mechanotransduction .
A major issue in sensory physiology is to understand how
Pain . Piezo . Kv . DRG neurons . Adaptation . Ion channels
stimulus information is transduced into an electrical signal and
encoded into a neural pulse code. Emerging evidence indi-
cates that receptors encoding property is due as much to the
Introduction auxiliary/support cells as to the sensory nerve ending. Thus,
information encoding depends on the cooperation of different
Somatosensory perception of the body involves the activation elements (Fig. 1): (i) the physicochemical communication
of primary sensory neurons whose cell bodies reside within between auxiliary cells and the sensory nerve ending, both
dorsal root ganglia (DRG). Perception from cranial structures being potentially mechanosensitive, (ii) the nature of the
(e.g., the face, oral cavity, and dura mater) is transmitted by mechanotransducer channels, properties of which shape the
trigeminal sensory neurons, which are functionally and mor- receptor potential, and (iii) the properties of voltage-gated ion
phologically homologous to DRG neurons. Mechanoreceptors channels that operate at subthreshold voltage range and mod-
ulate receptor potential and spiking.
J. Hao (*) : C. Bonnet : M. Amsalem : J. Ruel : P. Delmas The input signal of the primary sensory neuron, the recep-
Aix-Marseille-Universit, CNRS, Centre de Recherche en
tor potential, is generated following activation of
Neurobiologie et Neurophysiologie de Marseille, UMR 7286,
CS80011, Bd Pierre Dramard, 13344 Marseille Cedex 15, France mechanotransducer channels located at the sensory nerve
e-mail: jizhe.hao@univ-amu.fr ending. Existing data about these channel proteins are
110 Pflugers Arch - Eur J Physiol (2015) 467:109119

Fig. 1 Schematic representation of transduction and encoding by of the receptor potential. Moreover, mechanoreceptors encompass spe-
mechanoreceptors. Mechanotransduction takes place at sensory nerve cialized auxiliary or support cells that are mechanosensitive and actively
ending. Deformation of the skin opens mechanosensitive channels modulate the activity of the sensory nerve terminal, through chemical
(MSC) localized at the nerve terminal. The net ionic influx through and/or physical interactions. Integration of these different sensory mech-
excitatory (cationic) and inhibitory (potassium) MSCs generates the anisms results in specific discharge patterns including rapidly adapting
receptor potential, which may be amplified or repressed by voltage- (RA), slowly adapting (SA), and sustained (mechanonociceptor) firing.
gated channels operating in the subthreshold voltage range (gain system). Skin-nerve recordings: unpublished data from Jrme Ruel, Valentine
Once AP threshold is reached, the change in membrane potential is Bouvier, and Marcel Crest
transformed into an AP code, frequency of which reflects the amplitude

consistent with them possessing a unique electrical signature. 62, 92]. Furthermore, the depolarization initiated by
The parameters of the receptor potential such as amplitude and mechanotransducer channels mobilizes a set of voltage-gated
duration depend remarkably on the properties of these channels [36, 38, 91] localized close to the transducer site,
mechanotransducer channels. Stimulus perception also relies which amplify or repress the transducer signals, adding an-
on the structure of the nerve ending. By comparison with other level of control of the excitability of sensory nerve
nociceptors and thermoreceptors, which are all free nerve endings. These elements, alone or in combination, confer
endings [5, 75], nearly all mechanoreceptors have specialized specific mechanical thresholds and discharge patterns to the
endings consisting of a nonneural capsule surrounding the different subtypes of mechanoreceptors.
terminal and making, in some cases, synapse-like connections
[31, 81]. These structures could act as mechanical filters as
well as chemical modulators via neurotransmitter release, and Encoding properties of cutaneous mechanoreceptors
thereby contribute to the modulation of receptor potential
generation and firing activity of mechanoreceptors [68, 78]. DRG neurons are pseudo-unipolar, with one axonal branch
An elegant example of such interaction has been provided that extends to the periphery and another branch that forms
recently with the demonstration that Merkel cells tune the synapses with second-order neurons in the spinal cord
activity of touch receptors through active mechanisms [47, (Fig. 1). Touch sensations rely on particular DRG neurons
Pflugers Arch - Eur J Physiol (2015) 467:109119 111

that fall into two general categories, low-threshold mechano- favors direct activation of a mechanically activated channel.
receptors (LTMRs) that react to innocuous mechanical stimu- When recorded using CsCl-based pipette solution to block K+
lation and high-threshold mechanoreceptors (HTMRs) that currents, MS currents in DRG neurons exhibit reversal poten-
respond to harmful mechanical stimuli. The mechanical tial near 0 mV [15, 25, 34, 36, 65, 66]. Studies of ion
threshold represents the minimum intensity of stimulation selectivity indicate that MS currents are carried nonselectively
required to generate an AP in the nerve fiber. Once threshold by cations, including Na+, K+, and Ca2+ ions [65]. This is
has been reached, the change in membrane potential produced consistent with the selectivity of Piezo2 and TRPA1 cation
by the sensory stimulus is transformed into an AP code, the channels, which are among the potential molecular candidates
frequency of which reflects the amplitude of the receptor to sustain excitatory MS currents in rat and mouse DRG
potential. Thus, mechanoreceptors signal the rate at which neurons [15, 17, 29]. Other studies, however, have reported
the stimulus increases or decreases in intensity by changing the presence of a MS current in neurites and soma of mouse
their firing frequency. Among the LTMRs, the Pacinian DRG neurons with reversal potential (+60 mV) more akin to a
corpuscle appears to be the most sensitive. It detects small pure Na+ selective conductance [42, 54]. Whether this MS
vibrations and frictional displacement of the skin when the current differs fundamentally in its ion permeation mechanism
hand moves across an object. Meissners corpuscle is rather from those previously described or whether imperfect space
sensitive to abrupt changes in the shape of objects and clamp in remote areas may be the cause of this discrepancy
detects small ridges on an otherwise smooth surface. The remains to be established.
Merkel receptor provides an image of contours of objects,
its response being proportional to the surface curvature, Desensitization kinetics MS cation currents in DRG neurons
weak with gently curved objects and strong with sharply show functional heterogeneity. In response to sustained me-
curved objects. chanical stimulation, MS currents decline or desensitize,
Another important property of mechanoreceptors is the through closure of transduction channels (Fig. 2a). This mech-
adaptation. Mechanoreceptors with adaptation exhibit high- anism has been called relaxation [34]. Although all MS cur-
frequency firing activity at the onset of the mechanical stim- rents appear to decline during the static phase of the stimulus,
ulus but turn into silence during the static phase of the stim- they do so with different kinetics [25, 34]. Based on kinetics
ulus (Fig. 1). They signal the velocity and acceleration of the analysis, three main types of MS currents have been de-
stimulation. A number of receptors also activate (or reactivate) scribed: rapidly adapting ( = 26 ms), intermediately
at the end of the stimulus, conveying information about the adapting ( =1530 ms), and slowly adapting/persistent cur-
changing sensory environment to the brain (Fig. 1). LTMRs rent ( 200 ms) [25, 34, 66, 82]. MS current relaxation/
classified as rapidly adapting include the hair follicle, desensitization during sustained stimulation results from two
Meissners corpuscle, and Pacinian corpuscle, while those mechanisms, a process of inactivation that favors transition to
classified as slowly adapting include the Merkel cell-neurite a nonconducting state and a process of adaptation that makes
complex, Ruffini corpuscle, and C-fiber LTMRs [23]. the channel less sensitive to mechanical force [34, 82]. Be-
HTMRs that transmit pain exhibit little or no adaptation cause adapted MS channels can be reactivated immediately
[23]. The stimulus duration is signaled by persistent genera- after closure, the channels are not inactivated but their gating
tion of APs throughout the period of stimulation (Fig. 1). sensitivity had changed as the result of application of mechan-
ical stimulation. Channel adaptation therefore can be de-
scribed operationally as a simple translation of the activation
Properties and distribution of excitatory mechanosensitive curve of the transducer along the stimulus axis as described for
currents in sensory neurons auditory cells [27, 30, 44, 49, 69].

Ion selectivity The process by which mechanical energy is Distribution MS currents distribute differently in subsets of
converted into electrical signal requires the presence of DRG neurons. Based on electrophysiological and immuno-
mechanosensitive (MS) channels in the sensory cells. MS histochemical markers, rapidly and intermediately adapting
channels in DRG neurons are gated by pressure and other MS currents are mainly found in large diameter, LTMR-type
types of mechanical challenges, including osmotic shock, neurons lacking tetrodotoxin-resistant (TTX-R) Nav channels
stretch, and shear stress [11, 35, 37, 66, 80]. McCarter et al. and TRPV1. On the contrary, slowly adapting/persistent MS
[66] first described MS currents in DRG neurons using the currents are preferentially encountered in small-to-medium-
mechanoclamp technique, which consists of recording MS diameter neurons with properties reminiscent of C-LTMRs
currents in the whole-cell mode while poking the cell surface (TH + ), HTMRs (TTX-R + , TRPV1 ), and polymodal
via an electrically driven glass probe (see [35] for detailed nociceptors (TTX-R+, TRPV1+) [14, 24, 25, 34, 42]. There
methods). MS currents have a relatively short latency, which is good evidence to suggest that rapidly adapting MS currents
argues against activation of a second messenger cascade and recorded in some LTMRs are mediated by Piezo2 subunits
112 Pflugers Arch - Eur J Physiol (2015) 467:109119

Fig. 2 Mechanotransducer cation


currents encode duration and
speed of the mechanical stimulus.
a Families of rapidly adapting
(left panel) and slowly adapting
(right panel) MS current traces
evoked by a series of mechanical
steps in 0.7-m increments. b
Current-clamp responses evoked
by a long-lasting mechanical
stimulus in DRG neurons
expressing rapidly adapting (left
panel) and slowly adapting (right
panel) MS currents. Only slowly
adapting MS currents have the
capacity to generate tonic activity.
c. Velocity-related firing
properties of neurons expressing
rapidly adapting (left panel) and
slowly adapting (right panel)
currents. Probe velocities are
indicated

[15, 26, 28, 90]. Consistent with this prediction, recent data Encoding properties of excitatory mechanosensitive
indicates that Piezo2 conditional KO miceexhibit selective currents
deficit in gentle touch [92]. The nature of the slowly adapting
MS current found in HTMRs [14, 24, 25] and C-fiber LTMRs Differential distribution of excitatory MS currents in DRG
[19] remains elusive. Consistent with its expression pattern in neurons confers specific transducer responses to the different
small sensory neurons, TRPA1 has been put forward as a populations of sensory neurons. The biophysical properties of
potential candidate to mediate this current in nociceptors MS currents appear well suited to encode the various physical
[50, 89]. Mice lacking TRPA1 have been found to be deficient parameters of the mechanical stimulus, including threshold,
in the detection of noxious mechanical stimuli [9, 53], but this intensity, duration, and velocity (Fig. 2ac) [34, 82].
result could not be replicated [6]. Kwan et al. [53] went further
on to demonstrate a role of TRPA1 in mechanical hyperalgesia Mechanical threshold Due to limited control of applied me-
after bradykinin-induced inflammation. Thus, there is sub- chanical pressure, the activation threshold of MS currents is
stantial evidence for a role of TRPA1 in mediating responses by far the most difficult parameter to measure when tested in
to high-threshold mechanical stimuli in nociceptive neurons. cultured DRG neurons. Polymodal nociceptors, as defined by
However, further investigations are needed to determine concomitant activation by capsaicin and high-intensity me-
whether TRPA1 is a genuine mechanotransducer and to clar- chanical stimulation, have been proposed to express MS cur-
ify the existing discrepancies regarding its role in mammalian rents with mechanical threshold higher than that expressed in
mechanosensation. other classes of mechanosensory neurons [14, 24, 25]. These
Pflugers Arch - Eur J Physiol (2015) 467:109119 113

findings may suggest that MS current properties contribute to are unable to transduce stimulus frequencies above 16 Hz,
set the threshold difference that exists in vivo between whereas MS currents with little or no desensitization faithfully
HTMRs and LTMRs. Further support for the presence of follow high-frequency mechanical stimulation [34]. There-
low- and high-threshold mechanotransducer currents in vitro fore, the characteristics of MS currents that enable Meissners
is provided by radial stretch-based stimulation of cultured and Pacinian corpuscles to encode mechanical vibrations with
sensory neurons [7]. This assay has identified two populations specific frequencies remain to be determined.
of sensory neurons with different sensitivities to mechanical
stimulation, suggestive of the presence of transducer channels
with different mechanical thresholds [7]. The definite demon-
stration that MS currents in different DRG neuron subsets Properties and functions of inhibitory mechanosensitive
have different mechanical thresholds for activation awaits currents in sensory neurons
further studies in which changes in membrane tension can
be monitored precisely. In addition to MS cation currents, mechanical challenge of
sensory neurons has revealed MS currents selective for K+
Duration Fast- and intermediately adapting MS currents pro- ions [2, 36, 48]. DRG neurons express various types of K+
duce transient depolarizations in response to mechanical stim- channels linked to mechanosensation, including members of
ulation [34, 36, 82]. Consequently, DRG neurons expressing the KCNK and Kv1 families [2, 36, 41].
these MS currents generate phasic action potential discharges
in response to long-lasting mechanical stimulation. Thus, KCNK channels KCNK channels mediate K+-selective leak
these MS currents contribute to the adaptation of the firing currents, which regulate cell excitability through their influ-
response of sensory receptors (see Fig. 2b). Interestingly, the ence on the resting membrane potential. These channels are
phasic discharge pattern is mainly attributable to the properties known to be modulated by a variety of factors, such as
of MS currents because electrical stimulation evokes sustained endogenous ligands, anesthetics, temperature, and membrane
firing in these cells. In contrast, activation of slowly adapting/ tension [41, 59, 60, 76]. Three members of the KCNK family,
persistent MS currents causes tonic firing activity, thereby KCNK2, KCNK4, and KCNK10, are intrinsically
encoding the entire duration of the stimulus (Fig. 2b) [34, mechanosensitive in expression systems, and all of the three
82]. Although the relationship between in vitro and in vivo are expressed in DRGs [2, 48, 67, 72]. KCNK2, also called
data remains speculative, these findings suggest that slowly Trek1, is found exclusively in polymodal nociceptors respon-
adapting/persistent MS currents play a critical role in gener- sive to high pressure and extreme heat [2]. Trek1/ mice are
ating sustained activities of nociceptors in vivo. Conversely, more sensitive than wild-type mice to mechanical stimulation,
fast-adapting MS currents appear well suited to shape the suggesting that KCNK2 is important for tuning the
phasic discharges of LTMRs associated with innocuous touch. mechanosensitivity of polymodal nociceptors [2]. KCNK4,
Thus, these data show that sensory neurons in vitro display also known as Traak, is activated by both membrane stretch
MS currents with properties that are important for sensory and membrane crenation [59]. Kcnk4/ mice are hypersensi-
nerve encoding. tive to mechanical stimulation, a phenotype that is exacerbat-
ed while additionally deleting the kcnk2 gene [72]. Despite the
Velocity Fast- and intermediately adapting MS currents are remarkable phenotypes observed in transgenic mice, it is not
particularly sensitive to the variation of the stimulus velocity. yet clear whether KCNK channels act as mechanical trans-
Rapidly adapting MS channels respond in full when stimulat- ducers or as modulators of DRG neuron excitability.
ed by a pressure applied abruptly but are essentially inactive
during slowly applied or static forces. The quick reaction to an Kv1 channels Kv1 channels contribute to setting neuronal
abrupt stimulus and dumping of slowly applied forces indicate excitability in a variety of neurons [12]. A recent study report-
that these channels act as velocity detectors (Fig. 2c). This ed that Kv1.1 homomers and Kv1.1Kv1.2 heteromers are
property may be important for many LTMRs, such as the hair mechanically activated in DRG neurons [36]. The mechani-
follicle receptor, which is capable of detecting small changes cally activated K+ current displays slow kinetics of activation
in the dynamic stimulus parameters [10, 91]. The properties of and little or no inactivation (Fig. 3a). Kv1.1Kv1.2 channels
MS currents can also be relevant to mechanoreceptors that are are activated by indentation of the cell membrane in addition
specialized in detecting skin vibration. For example, to negative pressure in the patch pipette. Mechanical activa-
Meissners corpuscle is efficient in transducing low- tion occurs under physiological forces (10 mmHg) at both
frequency mechanical vibrations (3050 Hz), while the macroscopic and single-channel levels. Kv1.1-containing
Pacinian corpuscle is activated by disturbances at high fre- channels retain mechanosensitivity in excised patches, indi-
quency (250350 Hz) [46, 85]. However, due to relatively cating little contribution of cytoskeletal elements to mechan-
slow relief from desensitization, rapidly adapting MS currents ical sensitivity. Activation of Kv1.1 channels by mechanical
114 Pflugers Arch - Eur J Physiol (2015) 467:109119

challenge can be accounted for by a shift in the pore-opening currents in these cells activate more rapidly than the MS
equilibrium toward the open conformation. Membrane stretch Kv1.11.2 current, there is little distortion in the peak ampli-
therefore acts by facilitating voltage-dependent activation. tude of the receptor potential. Thus, the Kv1.11.2 current
Mechanistically, mechanosensitivity of Kv1.1 does not de- does not impede detection but regulates duration and frequen-
pend on a mechanical sensor that uses the energy of mem- cy of firing of LTMRs. Thus, functional connection between
brane tension to open the channel [15, 32, 94], but instead excitatory and inhibitory mechanotransducer channels is im-
makes the best use of the inherently stretch-sensitive proper- portant to set the properties of the receptor potential. The
ties of the voltage sensor [70]. modulation of either component in pathological conditions
The MS Kv1.1Kv1.2 current has been found in subsets of may disrupt this balance and makes animals hyper- or
DRG neurons that phenotypically correspond to HTMRs and hyposensitive to mechanical stimuli.
A-type LTMRs. Experimental evidence indicates that
HTMRs are mechanically tuned by the respective expression
of MS Kv1.11.2 and slowly adapting MS cation currents
whose respective inhibitory and excitatory influences modu- Modulation of receptor potential by subthreshold
late the net mechanical response (Fig. 3bd). MS Kv1.11.2 voltage-gated channels
shifts mechanical threshold for firing toward higher values
and concurrently reduces the duration of mechanically in- The net ionic current through MS channels brings the mem-
duced AP discharges. Thus, the function of MS Kv1.11.2 brane potential of mechanoreceptors toward the threshold for
in HTMRs is to regulate generator potential by balancing the triggering APs. Receptor potential therefore may activate
activity of MS excitatory channels. Translated to in vivo con- multiple intrinsic ionic conductances in the subthreshold
sideration, activation of MS Kv1.11.2 shifts the threshold for range. A series of studies has established that mechanical
noxious mechanoperception to higher values. By contrast, MS response depends on the balance of subthreshold currents
Kv1.11.2 has little impact on mechanical threshold proper- [38, 40, 91]. Activation of voltage-gated inward currents
ties of A-type LTMRs (Fig. 3d). Because excitatory MS amplifies receptor potential and prolongs their duration. In

Fig. 3 Mechanosensitive Kv1.1


current controls firing activity in
sensory neurons. a MS Kv1.11.2
current traces evoked by using a
series of mechanical stimuli of
increasing intensity (0.7 m) at a
holding potential of 30 mV. b
Mechanical stimulus inhibits
spontaneous firing activity in a
MS Kv1.11.2 current-
expressing sensory neuron. c
Total MS current traces deter-
mined at 30 mV in a putative
LTMR (left panel) and a
mechanonociceptive neuron
(right panel). Note the biphasic
shape of the total MS current in
the LTMR. d Current-clamp
responses evoked by mechanical
stimuli of 4.3 (upper panels) and
8.5 m (bottom panels) in cells
shown in c before (black traces)
and after (red traces) adding -
DTx, a specific blocker of Kv1.1
channels. Dashed lines indicate
the 0 mV level
Pflugers Arch - Eur J Physiol (2015) 467:109119 115

contrast, the activation of outward currents may counter re- outperformed control subjects when tested for vibrotactile
ceptor potential amplitude. acuity [38]. Thus, KCNQ4 acts as a brake on the excitation
of rapidly adapting Meissners corpuscles and hair follicle
Cav3.2 calcium channel The Cav3.2 T-type calcium channel afferents.
exhibits a low threshold of activation (60 mV) and pro-
duces Ca2+ current with rapid activation and inactivation Nav1.9 channel The voltage-gated Nav1.9 channel generates
phases in response to depolarization (Fig. 4b). Cav3.2 chan- an atypical Na+ current with hyperpolarized activation/
nels are strongly expressed in D-hair mechanoreceptors [39, inactivation properties, giving rise to a prominent persistent
87, 91] and to a lesser extent in C-tactile LTMRs [19] and Na+ current component at subthreshold voltages (Fig. 4a) [14,
nociceptors [8, 14]. The D-hair receptor has very low mechan- 16, 18, 21]. Nav1.9 is expressed in sensory enteric neurons
ical threshold and high sensitivity to changes in the velocity of [16, 51, 73, 74, 83] and all types of nociceptors, in which it co-
the mechanical stimulus [10]. Pharmacological inhibition as localizes with the slowly/persistent MS cation current [14].
well as genetic deletion of the Cav3.2 gene has been shown to Incidentally, Nav1.9 current has a crucial role in increasing
increase mechanical threshold and impair temporal firing of excitability of DRG nociceptors [3, 4, 16, 58] and enteric
D-hair receptors [91]. Altered properties are related to defi- neurons [16, 51, 73, 74, 83]. Upregulation of Nav1.9 current
ciency in receptor potential integration, since neither abnormal is particularly evident upon inflammation [58, 84]. For that
mechanotransducer current nor damaged nerve terminal struc- reason, Nav1.9 plays a permissive role in the generation of
ture was observed in Cav3.2 knockout mice. Thus, T-type mechanical pain hypersensitivity, both in subacute and chron-
calcium channels serve as subthreshold amplifier and appear ic inflammatory pain models [55]. It is also required for
to contribute to explain the high sensitivity of D-hair mecha- normal gut mechanosensation [13, 64] and for the develop-
noreceptors to moving stimuli. ment of the hypersensitivity of colonic afferents to mechanical
stimuli under inflammatory conditions [13, 40]. Thus, Nav1.9
KCNQ4 channel The Kv7.4 channel subunit (KCNQ4), a endows nociceptors with a subthreshold-activating inward
member of the family of voltage-gated K+ channel subunits current that can amplify depolarizing drive induced by MS
(Kv7.1Kv7.5) that are encoded by the KCNQ genes channels, a possible molecular mechanism for mechanical
(KCNQ15) [20], has been found essential to tune firing hyperalgesia (Fig. 4c).
activity of LTMRs, including Meissners corpuscles and lan-
ceolate and circular nerve endings [38]. KCNQ4 is a low-
threshold, slow activating, and noninactivating current that
typically plays a part in regulating the membrane potential Contribution of nerve ending structures
of various cell types [52]. The presence of the protein near the to mechanotransduction
mechanotransduction site suggests a role in the integration
process of receptor potential. Genetic deletion of the Kcnq4 Many mechanoreceptors exhibit specialized nerve endings.
gene in mice enhances mechanosensitivity and alters the Meissners and Pacinian corpuscles are encapsulated, whereas
frequency response of rapidly adapting mechanoreceptors. Merkel cell-neurite complex displays a synapse-like contact
Human subjects with loss of function mutation of KCNQ4 without forming a distinct encapsulated structure [31, 71, 81].

Fig. 4 Subthreshold channels regulate receptor potential amplitude. a evoked by 100-ms test pulses in a small nociceptive DRG neuron. Right
Properties of recombinant Nav1.9. Left panel: Nav1.9 current traces panel: corresponding current-voltage relationship. c Responses to me-
evoked by depolarizing voltage steps in a mouse Nav1.9/ DRG chanical stimulation in a DRG neuron before and after inhibition of
neuron 24 h post-transfection with a hNav1.9 clone. Right panel: corre- Nav1.9. Unpublished data from Muriel Amsalem
sponding current-voltage relationship. b Left panel: native Cav3.2 current
116 Pflugers Arch - Eur J Physiol (2015) 467:109119

The function of auxiliary-support cells in these specialized silencing of Merkel cells abolishes firing during the static
structures has long been debated. The emerging concept en- phase of the stimulus without affecting the dynamic response
visions a key role for auxiliary cells in mechanosensory [62] (Fig. 5a). These results demonstrate that Merkel cells
responses. directly activate the sensory fiber to drive the sustained firing.
Whether Merkel cells are intrinsic mechanosensory structures
has been demonstrated recently. A trio of papers [47, 62, 92]
Merkel cells are mechanosensory cells conjointly revealed that Merkel cells are mechanosensitive
and express the cationic Piezo2 channel. Selectively knocking
The Merkel cell-neurite complex is formed by the ending of out Piezo2 in Merkel cells abolishes the firing activity in the
myelinated, low-threshold nerve fibers (A type) and special- sensory fiber during the static phase of the mechanical stim-
ized epidermal cells, the so-called Merkel cells (Fig. 5a). ulation. Therefore, Merkel cells can be considered to act
These mechanoreceptors are enriched in touch-sensitive re- presynaptically to the sensory fiber. Many studies support
gions of the skin, including the fingertips, whisker follicles, the idea that Merkel cells can release neuroactive substances,
and touch domes [61]. Mechanical indentation of the Merkel including glutamate and neuropeptides. These cells form
cell-neurite complex generates a slowly adapting response synapse-like structures with the nerve endings and encompass
(SA1) characterized by high-frequency firing at the onset of many components of the presynaptic machinery for synaptic
the mechanical stimulation and a sustained low-frequency transmission, including SNARE-complex proteins,
firing during the static phase [45]. Genetic ablation of Merkel synaptotagmins, and voltage-gated Ca2+ channels [31, 33,
cells has been shown to turn SA1 activity into transient firing 61]. Which molecule(s) is (are) released during Merkel cell
[62, 63], demonstrating that Merkel cells are necessary for the stimulation and what the nature of the receptors on the post-
integrity of the sensory response. Furthermore, optogenetic synaptic neuronal membrane is, remain to be established.

Fig. 5 Nonneuronal receptor cells contribute to the encoding properties whereas normal (encapsulated) receptor classically exhibits receptor po-
of mechanoreceptors. a The Merkel cell-nerve receptor complex. Activa- tential with biphasic on-off time course. Unexpectedly, change in receptor
tion of MS Piezo2 in Merkel cells causes calcium mobilization, which in potential shape in the decapsulated Pacinian corpuscle does not translate
turn triggers the release of neuromodulators that regulate firing in the to firing discharge as the afferent fiber still exhibits on-off pattern.
postsynaptic sensory nerve fiber. b The Pacinian corpuscle. Figures adapted from [43, 62, 68, 92]
Decapsulated Pacinian corpuscle displays sustained receptor potential
Pflugers Arch - Eur J Physiol (2015) 467:109119 117

Whether nerve terminals send reciprocal messages back to the Concluding remarks
Merkel cells is also an important question to be addressed.
This is a time of excitation for those people working on
mechanosensation. Breakthroughs in the field have been nu-
Pacinian corpuscles: mechanical filter and chemical merous in recent time. Models of the mechanisms used to
modulator convert mechanical energy into electrical signals have appeared
[49, 86, 90]. Prospects for future research include expanding
Pacinian corpuscles are categorized as type II RA mechano- our understanding of the molecular basis of mechanical sensi-
receptors, whose firing activity is observed during the dynam- tivity and adaptation of mechanoreceptors. At play here are the
ic phase of the mechanical stimulus but not the static one [85]. molecular nature and properties of mechanotransducer chan-
Like Meissners corpuscles, Pacinian corpuscles respond to nels, but the function of the receptor macroscopic organization
mechanical stimuli at the onset and offset of stimuli. However, has to be considered carefully. Auxiliary cells have now be-
Pacinian corpuscles exhibit larger receptive fields and elevat- come mechanosensory cells in their own. Can we apply what
ed sensitivity to high-frequency vibration. Although the exact we learnt about Merkel receptors to other encapsulated recep-
molecular mechanisms of force transduction within the tors? Can this complex auxiliary cell/neuronal relationship
Pacinian corpuscle are still unknown, several studies have account for much of the relative sophistication of vertebrate
highlighted the contribution of the corpuscle structure to the mechanotransduction? At the molecular level, if the Piezo2
receptor response [68, 78, 85]. Ultrastructural studies revealed channel is required for touch-evoked responses in vivo, what
that each corpuscle is innervated by a single myelinated A then mediates mechanonociception? What is the exact role of
fiber enclosed by inner-core hemi-lamellae originated from mechanosensitive voltage-gated channels in sensory transduc-
Schwann cells, which in turn are enveloped by fibrous con- tion and encoding? Surely, the next few years will bring
nective tissue [79, 93]. This layered construction produces an groundbreaking progress in our understanding of molecular
onion-like appearance in cross sections that displays a great mechanisms of mechanotransduction.
elasticity. By measuring the radial displacement of the lamel-
lae during compression, it has been shown that the static
component of lamella displacement declines sensibly from Acknowledgments We thank all lab members for their contributions
and comments on this manuscript. The work from our lab is supported by
the periphery to the center of the corpuscle, whereas the the Centre National de la Recherche Scientifique (CNRS) and by grants
dynamic component reaches the axon at the core of the from the Agence Nationale de la Recherche (ANR-08-MNPS-025-02,
corpuscle, evoking a receptor potential from the innervating ANR-08-GENO-027-02, ANR-09-MNPS-037-01), the Fondation pour
axon [43]. This working hypothesis was substantiated by la Recherche Mdicale (quipes FRM 2013 DEQ20130326482), and the
Human Frontier Science Program (RGP0063/2014). J.H. is supported by
experiments in which the removal of the corpuscle lamella a postdoc fellowship from the FRM.
generates a sustained receptor potential in response to a steady
mechanical stimuli [68] (Fig. 5b). Intriguingly, despite the
maintained depolarization evoked at the nerve terminal, the
axon still fired phasically at the onset of the stimulation but not
References
during the static part of the sustained indentation stimulus.
This observation argues for other mechanisms of adaptation
that prevent repetitive impulses [68]. Two mechanisms have 1. Abraira VE, Ginty DD (2013) The sensory neurons of touch. Neuron
79:618639
been put forward: inactivation of the spike-generating system 2. Alloui A et al (2006) TREK-1, a K+ channel involved in polymodal
[68] and regulation of axonal excitation through the effects of pain perception. Embo J 25:23682376
neurotransmitters released from the lamella structure. Indeed, 3. Baker MD (2005) Protein kinase C mediates up-regulation of tetro-
the GABA release machinery has been identified in the inner- dotoxin-resistant, persistent Na+ current in rat and mouse sensory
neurones. J Physiol 567:851867
core lamella and GABA receptor antagonists, such as 4. Baker MD et al (2003) GTP-induced tetrodotoxin-resistant Na+
gabazine and picrotoxin, have been shown to convert the current regulates excitability in mouse and rat small diameter sensory
phasic discharge of the Pacinian corpuscle into a sustained neurones. J Physiol 548:373382
one [7779]. In addition, the glutamate receptor blocker 5. Basbaum AI et al (2009) Cellular and molecular mechanisms of pain.
Cell 139:267284
kynurenate strongly reduced the static spikes. Together, these 6. Bautista DM et al (2006) TRPA1 mediates the inflammatory actions
results suggest that GABA, released from the lamellar cells of of environmental irritants and proalgesic agents. Cell 124:12691282
the capsule, can inhibit the glutamatergic excitation during the 7. Bhattacharya MR et al (2008) Radial stretch reveals distinct popula-
static phase of the mechanical stimulation. Like for the Merkel tions of mechanosensitive mammalian somatosensory neurons. Proc
Natl Acad Sci U S A 105:2001520020
receptor, the chemical communication between auxiliary la- 8. Bourinet E et al (2005) Silencing of the Cav3.2 T-type calcium
mellar cells and the nerve ending appears crucial for the rapid channel gene in sensory neurons demonstrates its major role in
adaptation response of the Pacinian corpuscle. nociception. EMBO J 24:315324
118 Pflugers Arch - Eur J Physiol (2015) 467:109119

9. Brierley SM et al (2011) TRPA1 contributes to specific mechanically 35. Hao J, Delmas P (2011) Recording of mechanosensitive currents
activated currents and sensory neuron mechanical hypersensitivity. J using piezoelectrically driven mechanostimulator. Nat Protoc 6:
Physiol 589:35753593 979990
10. Brown AG, Iggo A (1967) A quantitative study of cutaneous recep- 36. Hao J et al (2013) Kv1.1 channels act as mechanical brake in the
tors and afferent fibres in the cat and rabbit. J Physiol 193:707733 senses of touch and pain. Neuron 77:899914
11 . C h e n g C M e t a l ( 2 0 1 0 ) P r o b i n g l o c a l i z e d n e u r a l 37. Hao J et al (2013) Piezo-electrically driven mechanical stimulation of
mechanotransduction through surface-modified elastomeric matri- sensory neurons. Methods Mol Biol 998:159170
ces and electrophysiology. Nat Protoc 5:714724 38. Heidenreich M et al (2012) KCNQ4 K (+) channels tune mechano-
12. Coetzee WA et al (1999) Molecular diversity of K+ channels. Ann N receptors for normal touch sensation in mouse and man. Nat Neurosci
Y Acad Sci 868:233285 15:138145
13. Copel C et al (2013) The Nav1.9 channel regulates colonic motility in 39. Hilaire C et al (2012) Neurotrophin-4 modulates the
mice. Front Neurosci 7:58 mechanotransducer Cav3.2 T-type calcium current in mice down-
14. Coste B, Crest M, Delmas P (2007) Pharmacological dissection and hair neurons. Biochem J 441:463471
distribution of NaN/Nav1.9, T-type Ca2+ currents, and mechanically 40. Hockley JR et al (2014) Multiple roles for NaV1.9 in the activation of
activated cation currents in different populations of DRG neurons. J visceral afferents by noxious inflammatory, mechanical, and human
Gen Physiol 129:5777 disease-derived stimuli. Pain 155:19621975
15. Coste B et al (2010) Piezo1 and Piezo2 are essential components of 41. Honore E (2007) The neuronal background K2P channels: focus on
distinct mechanically activated cation channels. Science 330:5560 TREK1. Nat Rev Neurosci 8:251261
16. Coste B et al (2004) Gating and modulation of presumptive NaV1.9 42. Hu J, Lewin GR (2006) Mechanosensitive currents in the neurites of
channels in enteric and spinal sensory neurons. Mol Cell Neurosci cultured mouse sensory neurones. J Physiol 577:815828
26:123134 43. Hubbard SJ (1957) The mechanical behaviour of Pacinian corpus-
17. Coste B et al (2012) Piezo proteins are pore-forming subunits of cles. J Physiol 137:40P42P
mechanically activated channels. Nature 483:176181 44. Hudspeth AJ (2014) Integrating the active process of hair cells with
18. Cummins TR et al (1999) A novel persistent tetrodotoxin-resistant cochlear function. Nat Rev Neurosci 15:600614
sodium current in SNS-null and wild-type small primary sensory 45. Iggo A, Muir AR (1969) The structure and function of a slowly
neurons. J Neurosci 19:RC43 adapting touch corpuscle in hairy skin. J Physiol 200:763796
19. Delfini MC et al (2013) TAFA4, a chemokine-like protein, modulates 46. Iggo A, Ogawa H (1977) Correlative physiological and morpholog-
injury-induced mechanical and chemical pain hypersensitivity in ical studies of rapidly adapting mechanoreceptors in cats glabrous
mice. Cell Rep 5:378388 skin. J Physiol 266:275296
20. Delmas P, Brown DA (2005) Pathways modulating neural KCNQ/M 47. Ikeda R et al (2014) Merkel cells transduce and encode tactile stimuli
(Kv7) potassium channels. Nat Rev Neurosci 6:850862 to drive abeta-afferent impulses. Cell 157:664675
21. Delmas P, Coste B (2003) Na+ channel Nav1.9: in search of a gating 48. Kang D, Kim D (2006) TREK-2 (K2P10.1) and TRESK (K2P18.1)
mechanism. Trends Neurosci 26:5557 are major background K+ channels in dorsal root ganglion neurons.
22. Delmas P, Coste B (2013) Mechano-gated ion channels in sensory Am J Physiol Cell Physiol 291:C138C146
systems. Cell 155:278284 49. Kawashima Y et al (2014) Transmembrane channel-like (TMC)
23. Delmas P, Hao J, Rodat-Despoix L (2011) Molecular mechanisms of genes are required for auditory and vestibular mechanosensation.
mechanotransduction in mammalian sensory neurons. Nat Rev Pflugers Arch, this issue
Neurosci 12:139153 50. Kerstein PC et al (2009) Pharmacological blockade of TRPA1 in-
24. Drew LJ et al (2007) High-threshold mechanosensitive ion channels hibits mechanical firing in nociceptors. Mol Pain 5:19
blocked by a novel conopeptide mediate pressure-evoked pain. PLoS 51. Korogod SM, Osorio N and Delmas P (2014) Dynamic excitation
One 2:e515 states and firing patterns are controlled by sodium channel kinetics in
25. Drew LJ, Wood JN, Cesare P (2002) Distinct mechanosensitive myenteric neurons. A stimulation study. Channels (Austin) In press
properties of capsaicin-sensitive and -insensitive sensory neurons. J 52. Kubisch C et al (1999) KCNQ4, a novel potassium channel
Neurosci 22:RC228 expressed in sensory outer hair cells, is mutated in dominant deaf-
26. Dubin AE et al (2012) Inflammatory signals enhance piezo2- ness. Cell 96:437446
mediated mechanosensitive currents. Cell Rep 2:511517 53. Kwan KY et al (2006) TRPA1 contributes to cold, mechanical, and
27. Effertz T, Scharr AL and Ricci AJ (2014) The how and why of chemical nociception but is not essential for hair-cell transduction.
identifying the hair cell mechano-electrical transduction channel. Neuron 50:277289
Pflugers Arch, this issue 54. Lechner SG et al (2009) Developmental waves of mechanosensitivity
28. Eijkelkamp N et al (2013) A role for Piezo2 in EPAC1-dependent acquisition in sensory neuron subtypes during embryonic develop-
mechanical allodynia. Nat Commun 4:1682 ment. EMBO J 28:14791491
29. Eijkelkamp N, Quick K, Wood JN (2013) Transient receptor potential 55. Lolignier S et al (2011) Nav1.9 channel contributes to mechanical
channels and mechanosensation. Annu Rev Neurosci 36:519546 and heat pain hypersensitivity induced by subacute and chronic
30. Fettiplace R, Kim KX (2014) The physiology of mechanoelectrical inflammation. PLoS One 6:e23083
transduction channels in hearing. Physiol Rev 94:951986 56. Lolignier S, Eijkelkamp N and Wood JN (2014) Mechanical
31. Fleming MS, Luo W (2013) The anatomy, function, and develop- allodynia. Pflugers Arch, this issue
ment of mammalian Abeta low-threshold mechanoreceptors. Front 57. Lumpkin EA, Caterina MJ (2007) Mechanisms of sensory transduc-
Biol (Beijing) 8:408420 tion in the skin. Nature 445:858865
32. Gillespie PG, Muller U (2009) Mechanotransduction by hair cells: 58. Maingret F et al (2008) Inflammatory mediators increase Nav1.9
models, molecules, and mechanisms. Cell 139:3344 current and excitability in nociceptors through a coincident detection
33. Haeberle H et al (2004) Molecular profiling reveals synaptic release mechanism. J Gen Physiol 131:211225
machinery in Merkel cells. Proc Natl Acad Sci U S A 101:14503 59. Maingret F et al (1999) TRAAK is a mammalian neuronal mechano-
14508 gated K+ channel. J Biol Chem 274:13811387
34. Hao J, Delmas P (2010) Multiple desensitization mechanisms of 60. Maingret F et al (1999) Mechano- or acid stimulation, two interactive
mechanotransducer channels shape firing of mechanosensory neu- modes of activation of the TREK-1 potassium channel. J Biol Chem
rons. J Neurosci 30:1338413395 274:2669126696
Pflugers Arch - Eur J Physiol (2015) 467:109119 119

61. Maksimovic S, Baba Y, Lumpkin EA (2013) Neurotransmitters and 78. Pawson L et al (2009) GABAergic/glutamatergic-glial/neuronal in-
synaptic components in the Merkel cell-neurite complex, a gentle- teraction contributes to rapid adaptation in pacinian corpuscles. J
touch receptor. Ann N Y Acad Sci 1279:1321 Neurosci 29:26952705
62. Maksimovic S et al (2014) Epidermal Merkel cells are 79. Pawson L, Slepecky NB, Bolanowski SJ (2000)
mechanosensory cells that tune mammalian touch receptors. Nature Immunocytochemical identification of proteins within the Pacinian
509:617621 corpuscle. Somatosens Mot Res 17:159170
63. Maricich SM et al (2009) Merkel cells are essential for light-touch 8 0. Po o l e K, Mo r o n i M an d L e w i n GR (2 0 1 4) S e n so r y
responses. Science 324:15801582 mechanotransduction at membrane-matrix interfaces. Pflugers
64. Mazet B (2014) Gastrointestinal motility and its enteric actors in Arch, this issue
mechanosensitivity: past and present. Pflugers Arch, this issue 81. Roudaut Y et al (2012) Touch sense: functional organization and
65. McCarter GC, Levine JD (2006) Ionic basis of a molecular determinants of mechanosensitive receptors. Channels
mechanotransduction current in adult rat dorsal root ganglion neu- (Austin) 6:234245
rons. Mol Pain 2:28 82. Rugiero F, Drew LJ, Wood JN (2010) Kinetic properties of mechan-
66. McCarter GC, Reichling DB, Levine JD (1999) Mechanical trans- ically activated currents in spinal sensory neurons. J Physiol 588:
duction by rat dorsal root ganglion neurons in vitro. Neurosci Lett 301314
273:179182 83. Rugiero F et al (2003) Selective expression of a persistent
67. Medhurst AD et al (2001) Distribution analysis of human two pore tetrodotoxin-resistant Na+ current and NaV1.9 subunit in myenteric
domain potassium channels in tissues of the central nervous system sensory neurons. J Neurosci 23:27152725
and periphery. Brain Res Mol Brain Res 86:101114 84. Rush AM, Waxman SG (2004) PGE2 increases the tetrodotoxin-
68. Mendelson M, Lowenstein WR (1964) Mechanisms of receptor resistant Nav1.9 sodium current in mouse DRG neurons via G-
adaptation. Science 144:554555 proteins. Brain Res 1023:264271
69. Michalski N and Petit C (2014) Genetics of auditory mechano- 85. Sato M (1961) Response of Pacinian corpuscles to sinusoidal vibra-
electrical transduction. Pflugers Arch, this issue tion. J Physiol 159:391409
70. Morris CE (2011) Voltage-gated channel mechanosensitivity: fact or 86. Schafer WR (2014) Mechanosensory molecules and circuits in C.
friction. Front Physiol 2:25 elegans. Pflugers Arch, this issue
71. Nakatani M et al (2014) Mechanotransduction in epidermal Merkel 87. Swayne LA, Bourinet E (2008) Voltage-gated calcium channels in
cells. Pflugers Arch, this issue chronic pain: emerging role of alternative splicing. Pflugers Arch
72. Noel J et al (2009) The mechano-activated K+ channels TRAAK and 456:459466
TREK-1 control both warm and cold perception. EMBO J 28:1308 88. Tsunozaki M, Bautista DM (2009) Mammalian somatosensory
1318 mechanotransduction. Curr Opin Neurobiol 19:362369
73. Osorio N, Korogod S, Delmas P (2014) Specialized functions of 89. Vilceanu D, Stucky CL (2010) TRPA1 mediates mechanical currents
Nav1.5 and Nav1.9 channels in electrogenesis of myenteric neurons in the plasma membrane of mouse sensory neurons. PLoS One 5:
in intact mouse ganglia. J Neurosci 34:52335244 e12177
74. Padilla F et al (2007) Expression and localization of the Nav1.9 90. Volkers L, Mechioukhi Y and Coste B (2014) Piezo channels: from
sodium channel in enteric neurons and in trigeminal sensory endings: structure to function. Pflugers Arch, this issue
implication for intestinal reflex function and orofacial pain. Mol Cell 91. Wang R, Lewin GR (2011) The Cav3.2 T-type calcium channel
Neurosci 35:138152 regulates temporal coding in mouse mechanoreceptors. J Physiol
75. Patapoutian A et al (2003) ThermoTRP channels and beyond: mech- 589:22292243
anisms of temperature sensation. Nat Rev Neurosci 4:529539 92. Woo SH et al (2014) Piezo2 is required for Merkel-cell
76. Patel AJ et al (1998) A mammalian two pore domain mechano-gated mechanotransduction. Nature 509:622626
S-like K+ channel. EMBO J 17:42834290 93. Zelena J (1978) The development of Pacinian corpuscles. J
77. Pawson L, Pack AK, Bolanowski SJ (2007) Possible glutaminergic Neurocytol 7:7191
interaction between the capsule and neurite of Pacinian corpuscles. 94. Zhao H, Sokabe M (2008) Tuning the mechanosensitivity of a BK
Somatosens Mot Res 24:8595 channel by changing the linker length. Cell Res 18:871878