Transient Receptor Potential Channels and Mechanosensation

NE36CH23-Wood ARI 26 May 2013 10:25
V I E W
E Review in Advance first posted online
R
on June 5, 2013. (Changes may
S
still occur before final publication
online and in print.)
C E
I N
A
D V A
Transient Receptor
Potential Channels
and Mechanosensation
by University of Massachusetts - Amherst on 06/13/13. For personal use only.
Niels Eijkelkamp,1 Kathryn Quick,2

Annu. Rev. Neurosci. 2013.36. Downloaded from www.annualreviews.org
and John N. Wood2

1
Laboratory of Neuroimmunology and Developmental Origins of Disease, University
Medical Center Utrecht, 3584 EA Utrecht, The Netherlands;
email: N.Eijkelkamp@umcutrecht.nl
2
Wolfson Institute for Biomedical Research, University College London, London WC1
6BT United Kingdom; email: J.Wood@ucl.ac.uk, K.quick@ucl.ac.uk
Annu. Rev. Neurosci. 2013. 36:519–46 Keywords

The Annual Review of Neuroscience is online at
neuro.annualreviews.org mechanotransduction, hearing, touch, pain
This article’s doi: Abstract
10.1146/annurev-neuro-062012-170412
Transient receptor potential (TRP) channels act as sensors for a range
Copyright c 2013 by Annual Reviews.
All rights reserved of stimuli as diverse as light, sound, touch, pheromones, and tissue
damage. Their role in mechanosensation in the animal kingdom, iden-
tified by gene ablation studies, has raised questions about whether they
are directly mechanically gated, whether they act alone or in concert
with other channels to transduce mechanical stimuli, and their relative
importance in various functions and disease states in humans. The abil-
ity of these channels to form heteromultimers and interact with other
ion channels underlies a range of cell-specific functions in different
cell types. Here we overview recent advances in this rapidly expanding
field, focusing on somatosensation, hearing, the cardiovascular system,
and interactions between TRP channels and other proteins involved in
mechanoelectrical signaling.
519
Changes may still occur before final publication online and in print
an important role in calcium signaling. Some

Contents TRP channels are also important for magne-
sium homeostasis, for example, TRPM6 (Xie
INTRODUCTION . . . . . . . . . . . . . . . . . . 520
et al. 2011) and other magnesium permeant
TOUCH AND MECHANICAL
channels (TRPM2, TRPV1/2). TRP channels
PAIN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 523
generally have six transmembrane domains with
HEARING . . . . . . . . . . . . . . . . . . . . . . . . . . . 524
intracellular N and C termini, with a contribu-
INVERTEBRATES . . . . . . . . . . . . . . . . . . 525
tion by the S5–S6 transmembrane segments to
VERTEBRATES . . . . . . . . . . . . . . . . . . . . . 525
the cation-selective pore. These features com-
CARDIOVASCULAR SYSTEM . . . . . . 526
bined with voltage-dependent activity in some
KIDNEY
channels suggest an evolutionary link between
MECHANOTRANSDUCTION . . 530
TRP channels and the voltage-activated sodium
VISCERAL
and calcium channels that are central to the
MECHANOSENSATION . . . . . . . . 531
functioning of animal nervous systems. Thus,
TRP INTERACTIONS WITH

TRP channels may be not only the “doors of
OTHER PROTEINS AND

perception” through which external signals are
MECHANOTRANSDUCTION . . 531
detected at cellular and organismal levels but
TRP CHANNEL GATING
also the original building blocks of the electri-
MECHANISMS . . . . . . . . . . . . . . . . . . . 534
cal signaling system in animal nervous systems.
Membrane Perturbation and
The presence or absence of TRP channels is
Potential Direct Activation . . . . . . 534
characteristic of animals or plants, respectively
Indirect Activation . . . . . . . . . . . . . . . . . 535
(Ramsey et al. 2006).
FUTURE PROSPECTS. . . . . . . . . . . . . . 538
The subtypes of TRP channel are shown in
Figure 1, where structural features of the chan-
nels are graphically represented. In mammals,
INTRODUCTION there are broadly expressed structurally distinct
Transient receptor potential (TRP) channels subsets of channels, termed TRPC, (canonical
contribute to intracellular signaling in many channels; seven members) TRPV (vanilloid;
physiological systems and have been a focus six members), TRPA (ankyrin, 1 member),
of particular interest in studies of sensory TRPM (melastatin; seven members), TRPML
transduction. The first clue that such channels (mucolipin; three members), and TRPP
existed came from an electrophysiological (polycystin; three members) (Wu et al. 2010).
analysis of Drosophila by Cosens & Manning Channels both within and across structural
(1969), who found that a mutant fly showed subsets may be able to heteromultimerize to
impaired vision upon continuous illumination. provide an extraordinary diversity of channels
It took 20 years before the mutant gene was (Figure 2). For example, evidence indicates
cloned (Montell & Rubin 1989, Wong et al. the existence of TRPC heteromultimers as
1989), and only in 1991 were TRP proteins well as TRPC1/TRPV4, TRPC1/TRPP2,
defined as ion channels (Hardie 1991, 2011). and TRPV1/TRPA1 heteromultimers (Kobori
The first mammalian TRP homologues were et al. 2009, Ma et al. 2011a, Staruschenko et al.
cloned by Montell (Wes et al. 1995) and by 2010). The genetic diversity of the channels
Birnbaumer (Zhu et al. 1995) in 1995, and is further enhanced by the existence of splice
a role for this class of ion channels in all variants that could theoretically produce
types of sensory transduction has continued to increasingly complex repertoires of different
accumulate (Zhu 2011). In this review we focus channel subtypes. Splice variants with distinct
on TRP channels and mechanosensation. functions have been identified in TRPC3
TRP channels form multimeric cation- (Kim et al. 2012). A practical consequence of
selective complexes (usually tetramers) and play the broad expression of a range of different
520 Eijkelkamp · Quick · Wood
TRP channels is that the characterization of Pore region

the properties of a particular channel type
expressed in a cell line may be affected by
the presence of endogenous TRPs. Permissive
factors that regulate TRP channel activity have
also been found. For example, in pancreatic
acinar cells, Stim1 translocates TRPC1 into
the cell membrane to activate calcium influx
(Yuan et al. 2007). The various discrepancies
in the literature on the topic of TRP channel
activation may reflect the complexities of TRP
interactions in controlling activity.
TRP channels are found throughout the TRPC
animal kingdom, in yeast, fungi, worms, flies, TRPA
mice, and humans. In yeast, hyperosmotic stim-

TRPV
uli cause calcium movement from the vacuole
to the cytoplasm through the TRPY1 chan- TRPM
nel. Other fungi such as Candida albicans ex-
TRPP
press related TRPY proteins that can function-
ally substitute for TRPY1 as mechanosensors TRPML
in yeast (Zhou et al. 2005). Worms and flies
also express a range of TRP channels. For ex- Ankyrin Enzyme
TRP box
ample, Drosophila have the original TRP chan- repeat domain
nel and related TRP-like protein (TRPL) as Coiled-coil CaM- , IP3R- ER
well as 11 other TRP channels involved in a domain binding site retention
variety of sensations, some of which involve Figure 1
interactions with rhodopsin outside the con- Structure of transient receptor potential (TRP) channel families. The six TRP
text of light sensing (Fowler & Montell 2013, families differ in their amino and carboxyl termini. The TRPC (TRP canonical
Shen et al. 2011). Similarly, representatives of channel), TRPA (TRP ankyrin), and TRPV (TRP vanilloid) subfamilies
contain ankyrin repeat motifs present in tandem copies that contain elastic
all types of known TRP channels (17 in total)
properties, which may be relevant to mechanosensation. The TRP box is
are found in Caenorhabditis elegans, for which thought to be involved in gating and is present in TRPV, TRPM (TRP
roles in mechanosensation have been described melastatin), and TRPC subfamilies. TRPP (TRP polycystin) and TRPML
(Xiao & Xu 2011). (TRP mucolipin) specifically contain endoplasmic reticulum (ER) retention
Genetic evidence of a contribution to domains that may be important for their functional localization in intracellular
organelles. Members of the TRPC subfamily also contain a calmodulin
mechanosensation of a variety of TRP chan-
inositosol-1,4,5-tris-phosphate receptor binding domain at the carboxyl
nels is strong, as loss-of-function mutations in terminus that may be involved in channel gating.
organisms ranging from invertebrates to ze-
brafish, to mice and humans have been recorded (Drew et al. 2002), as does the non-TRP
(Zhu 2011). However, formal proof of a role for mechanotransducer Piezo2 (Coste et al. 2012,
these (or, indeed, any) channels is lacking, as Eijkelkamp et al. 2013). Cold and ligand-gated
mechanically gated ion channel activity in lipid TRP channel activity for TRPM8 in lipid bi-
bilayers of purified TRP proteins has not been layers conclusively demonstrates a role for this
observed. It is quite likely that such proof will channel in cold transduction (Zakharian et al.
never be obtained because a requirement for the 2010). By contrast, even though Piezo proteins
integrity of the cytoskeleton has been observed form ion channels in isolation in lipid bilayers,
with many mechanosensitive ion channel they may also require the actin cytoskeleton
systems. Sensory neuron mechanically gated to become mechanosensitive (Dubin et al.
ion channels depend on the actin cytoskeleton 2012).
www.annualreviews.org • TRP Channels and Mechanosensation 521
To make a compelling case for a mechan-

otransducing role, a number of criteria need to
be fulfilled:
1. Loss of expression of the channel should
result in a loss of mechanosensitivity.
2. Heterologous expression of the candidate
channel should result in the acquisition of
mechanosensitivity in a number of differ-
ent cellular environments.
3. The pharmacological and biophysical
properties of the candidate channel
should align with those of the endogenous
mechanotransducing current studied.
4. Modulators of mechanosensation at the
behavioral or electrophysiological levels

TRPC1
760 should show parallel effects on channel
activity.
302 5. The channel should, ideally, form a
mechanotransducing complex in a lipid
bilayer.
TRPC3
848 A critical role in mechanosensation does
not necessarily imply a role as a direct mechan-
921 otransducer. Recent studies in C. elegans have
shown an intimate relationship between the
793
ENaC channel DEG-1 and the TRPV channel
OSM9, where ENaC channels are mechan-
256
otransducers. By contrast, TRPV channels such
as OSM9 play an important role in downstream
Ankyrin Transmembrane Coiled-coil signaling events that result in behavior effects
repeat domain region
on mechanosensation (Geffeney et al. 2011,
Figure 2 Liedtke 2007a). In contrast to the situation in
Multimerization and splice variants increase TRP diversity. Many closely C. elegans, there is compelling evidence against
related members of the TRP superfamily of proteins form tetramers. a direct role for the ENaC set of acid-sensing
TRP channels form homomeric or heteromeric complexes (upper panel )
ion channels in mammalian somatosensation
depending on subunit types. Multimerization modulates the function,
subcellular localization, and biophysical properties of the interacting channels. (Kang et al. 2012, Raouf et al. 2012). The
The C-terminal region has been proposed to contribute to subunit assembly. evidence for ENaC channels as mechanotrans-
The different members of the TRP family can form many different ducers in shear-stress sensing is indirect, and
combinations, which increases the functional diversity among TRP channels. heterologous expression of mammalian ENaC
Channel activity has indicated that TRPC channels function as
channels as mechanotransducing channels has
heteromultimers, and we have recently shown that coexpression of TRPC6
with TRPC3 enhances mechanosensitivity. (Lower panel ) A schematic not been achieved. However, the evidence for
representation of predicted splice variants of two members of the TRPC ENaC family members as mechanotransducers
family, TRPC1 and TRPC3, to exemplify TRP diversity. The numbers in C. elegans is compelling (O’Hagan et al.
indicate the total number of amino acids of each individual splice variant. This 2005). Other C. elegans TRP family members
figure highlights that the existence of multiple splice variants of each TRP
such as TRP-4 also seem likely to be bona
family member even further increases the possible number of TRP heteromeric
complexes, which thus likely increases the functional diversity of TRPs. fide mechanotransducers, as indicated by
mutagenesis studies of the putative pore region
of this channel (Kang et al. 2010). Similarly,
TRPP polycystins that are involved in kidney
mechanosensation interact closely with K2P classes of inactivating mechanosensitive cur-

channels and respond to mechanical pressure to rents (Delmas et al. 2011, Drew et al. 2007).
enhance opening of these channels and protect Recently, two classes of mechanotransducing
against apoptosis (Peyronnet et al. 2012). candidates have also been linked to touch. The
novel mechanotransducer Piezo2 is required
for expression of rapidly adapting channels in
TOUCH AND MECHANICAL PAIN approximately 66% of the neurons that express
The ability to detect mechanical stimuli in- such channels (Coste et al. 2012). Antisense
volves TRP channels in many cell types. In knockdown of Piezo2 results in touch and al-
flies, most attention has focused on hearing lodynia deficits (Eijkelkamp et al. 2013).
rather than touch sensation, although Painless, Interestingly, a role for TRPC channels in
a TRP gene first identified in the Benzer lab light touch has also been described. When
does have a role in noxious mechanosensation TRPC3 is deleted, mechanosensory behavior of
in larvae and pressure sensing in the adult heart knockout mice is normal, but there is a change
(Sénatore et al. 2010, Tracey et al. 2003). In in kinetics of the mechanosensitive channels ex-
C. elegans, a role for TRPVs in touch sensa- hibited by sensory neurons (Quick et al. 2012).
tion has been established, and TRPA1 loss is as- However, deletion of TRPC3 together with
sociated with mechanosensory deficits. In con- TRPC6 results in a loss of sensitivity of 50% of
trast to human TRPA1, worm TRPA1 forms a the rapidly adapting mechanosensitive neurons
mechanosensitive channel when expressed het- and a deficit in light touch (Figure 3). Storch
erologously in eukaryotic cell lines (Kindt et al. et al. (2012a) showed that TRPC1 does not ex-
2007, Rugiero et al. 2010). press as a functional channel alone, although
On the basis of an in-depth mutagenesis trafficking of TRPC1 by STIM-1 results in a
study, TRP-4 found in ciliated sensory neu- functional channel (Yuan et al. 2007). TRPC1
rons also seems very likely to be a bona fide can also interact with TRPC3, -4, -5, -6, or -7,
mechanotransducer. TRP-4 (or TRP-N) chan- resulting in channels with lowered calcium per-
nel loss-of-function mutants do not move, con- meability (Storch et al. 2012a). When TRPC1
sistent with a mechanosensory role (Kang et al. is deleted in mice, light-touch behavioral re-
2010). Other channels, for example, Drosophila sponses are partially lost (Garrison et al. 2012).
PKD2 involved in mating behavior and ex- In addition, recordings of skin-nerve prepa-
pressed in mechanosensitive sensory cells, are ration showed that mechanical stimuli evoked
also candidate mechanosensors. Additionally, 50% fewer action potentials in slowly adapting
in zebrafish, inactivation of the unusual inte- Aβ fibers and rapidly adapting Aδ fibers associ-
gral kinase TRP channel TRPM7 leads to a loss ated with touch-sensitive Merkel cells and down
of escape responses upon mechanical stimula- hairs, respectively. Thus, TRPC1 may play a
tion in the mutant touchdown. However, sen- role, probably as a complex with other channels
sory neuron integrity and function are retained in light touch. However, mechanotransduction
in these animals, suggesting a downstream role deficits in isolated neurons have not yet been
for this particular channel (Low et al. 2011). identified.
Somatosensation in mammals involves spe- Noxious mechanosensation is associated
cialized sensory neurons that express different with a slowly adapting class of mechanosensing
types of mechanosensitive channels associated channels in sensory neurons (Drew et al. 2007).
with light touch or noxious mechanosensation Some evidence suggests that TRPA1, a known
(Delmas et al. 2011, Nilius & Honore 2012, mechanosensor in C. elegans (Kindt et al.
Wood & Eijkelkamp 2012). Rapidly adapt- 2007), plays a related role in mice. There is a
ing channels seem to be a hallmark of light- deficit in Randal-Sellito noxious mechanosen-
touch transducing neurons, whereas noxious sation in the TRPA1 null mutant (Andersson
mechanosensation has been linked to slower et al. 2009), and slowly adapting currents
a b c
von Frey Cotton swab Current types
0.8 5 100
*** *
4 80 *
Number of responses
0.6
50% threshold (g)
per 5 applicants
Small DRG (%)

3 60 No response
RA
0.4 * IA
2 40 SA
0.2
1 20
0 0 0
WT TRPC3/ TRPC3 TRPC6 WT TRPC3/ TRPC3 TRPC6 WT TRPC3/

TRPC6 KO KO TRPC6 KO KO (n=73) TRPC6

DKO DKO DKO
(n=86)
Figure 3
Innocuous touch sensation is attenuated in TRPC3/TRPC6 double knockout mice shown by (a) von Frey hairs and (b) response to a
cotton bud. (a) 50% threshold to mechanical stimulation using von Frey hairs in wild-type (WT) TRPC3/TRPC6 double knockout
(DKO), TRPC3 knockout (KO), and TRPC6 KO. (b) Responses of WT, TRPC3/TRPC6 DKO, TRPC3 KO, and TRPC6 KO mice
to a cotton bud applied to the plantar surface of the hind paw. (c) Small-diameter dorsal root ganglion (DRG) neurons had mechanically
activated currents, which could be classified on the basis of their adaptation kinetics to a static mechanical stimulus as rapidly adapting
(RA), intermediately adapting (IA), and slowly adapting (SA). A significant reduction in the number of neurons displaying RA currents
and an increase in number of nonresponsive neurons were observed in TRPC3/TRPC6 DKO mice (χ -square test, p < 0.05). See
Quick et al. 2012. ∗ , p < 0.05; ∗∗∗ , p < 0.01.
in a subset of nociceptive neurons are lost TRP channels in central information process-
(Vilceanu & Stucky 2010). Blockers of TRPA1 ing. Thus, spinal cord TRPV1 activation (Kanai
also inhibit mechanical firing (Kerstein et al. et al. 2005) leads to allodynia in some neu-
2009), and TRPA1 contributes to interme- ropathic pain models, and specific antagonists
diately adapting mechanosensory currents can reverse this form of mechanical sensitiza-
and mechanical hyperalgesia (Brierley et al. tion. Some research also claims that TRPC3
2011). Further support for a role for TRPA1 is centrally involved in synaptic transmission
in pain-related mechanosensation comes from (Hartmann et al. 2008), which could have ef-
Wei et al. 2012, who studied postoperative fects on some behavioral assays of mechanosen-
mechanical hyperalgesia in the rat, and Okubo sation.
et al. (2012), who established a role for TRPA1
in mouse mechanosensitization by hydrogen HEARING
sulfide (Okubo et al. 2012). Interestingly, a Hearing and balance are dependent on hair cells
heritable pain disorder has been mapped to within the inner ear. The mechanically sensitive
a point mutation in TRPA1 (Kremeyer et al. hair cell stereociliary bundle comprises 50–100
2010), and the overriding sensation associated stereocilia. Hair cells are arranged along the
with the gain-of-function channel is that of length of the cochlea and vary in their frequency
unbearable mechanical pain. The same channel sensitivity; cells responding to the highest fre-
shows enhanced activation by cold (one of the quencies are found at the base of the cochlea
initiating factors of pain attacks). (Figure 4). The kinetics of the mechanoelec-
Behavioral analysis of TRP mutants in trical transduction (MET) channels of cochlear
mechanosensation has also identified roles for outer hair cells also vary with an increase in
single channel conductance and channel num- pt ation

ber from low to high frequencies (Beurg et al. d ada
an
ce
2006). Similar to TRP channels, mechanically an
ct
activated channels are calcium permeant and
u
nd
can be blocked by Gd3+ and ruthenium red
co
48 kHz
32 kHz
e in
(Farris et al. 2004, Kroese et al. 1989, Marcotti
Increas
et al. 1999, Rusch et al. 1994). Despite heroic 8 kHz
efforts, the nature of the hair cell MET chan- 6 kHz
nels has still not been established.
24 kHz 64 kHz
INVERTEBRATES
12 kHz
In Drosophila, the genes Nanchung and inactive
are related to worm ocr and osm-9 proteins, 16 kHz
respectively. Both Nanchung and inactive are

Figure 4
found in the mechanosensory cilia of the chor-
Frequency-place map for the mouse cochlea. Hair cells along the length of the
dotonal organ (Kim et al. 2003), and Nanchung basilar membrane respond to differing sound frequencies creating a tonotopic
null Drosophila and inactive null Drosophila mu- gradient. Approximate locations for the highest response to certain frequencies
tants have ablated sound-evoked potentials are indicated. The conductance and kinetics of the mechanotransducer also
(Kim 2007, Kim et al. 2003). Nanchung and create a gradient from the apex to the basal end of the cochlea (figure adapted
from Viberg 2004, original data from Muller 2004).
inactive are localized to the cilia only when
both are present, indicating interactions be-
tween the two are required for functionality, tation increase from the apex to the basal region
even though each alone form mechanosensitive of the cochlea (Ricci et al. 2003). The tonotopic
channels when expressed in culture. gradients in the cochlea could be explained by
NOMPC or TRPN1 is found in the cilia a channel consisting of multiple subunits that
of chordotonal neurons in Drosophila (Liang vary in composition along the cochlear duct.
et al. 2011). Walker et al. (2000) reported The nonselective permeability, large conduc-
that NOMPC mutants displayed nearly tance, pharmacology, and ability to heteromul-
absent sound-evoked potentials but that a timerize suggest TRP channels as potential
small nonadapting mechanosensory current candidates for the MET channel; thus, a num-
remained, thus casting doubt over its role as the ber of TRP channels have been investigated.
mechanotransducer. However, the remaining Of the mammalian TRPs, TRPA1 has
nerve potentials have recently been attributed the most ankyrin repeats, a property shared
to gravity receptor cells, which supports with TRPN channels and that could be the
the possibility that NOMPC is a Drosophila gating spring proposed to be involved in
auditory transducer (Effertz et al. 2011). mechanotransduction in the hair cells. TRPA1
is expressed in mammalian hair cells and
is blocked by the same series of blockers
VERTEBRATES (amilorides, lanthanides, and ruthidium red)
Vertebrate hair cell transduction in the as found in the mechanotransduction channel
cochlea relies on tip links between stereocilia in hair cells (Nagata et al. 2005). Although
(Schwander et al. 2009) and mechanotrans- TRPA1 knockout mice do not show a behav-
duction channels within these stereocilia that ioral auditory or vestibular deficit, auditory
may be gated by a purely hypothetical elastic brain stem responses (ABRs) show that the
element termed “the gating spring” (Corey hearing of TRPA1−/− mice is more sensitive
& Hudspeth 1983). The amplitude of the than that of wild-type mice (Kwan et al. 2006).
mechanically gated current and speed of adap- However, in Drosophila, TRPA1 mutants
with a loss of mechanosensation normal in inner hair cells of mice (Steigelman et al.
mechanofunction was recovered with the in- 2011).
troduction of a TRPA1 mutant that has all the So far, TRPC3 and TRPC6 are the only
ankyrin repeats removed (Hwang et al. 2012). TRP channels linked to a deficit in the MET
The vertebrate TRPV4 channel is expressed currents in hair cells (Tadros et al. 2010, Quick
in hair cells of rodents (Liedtke et al. 2000, Shen et al. 2012). TRPC3 and TRPC6 are both
et al. 2006) and zebrafish (Amato et al. 2012). expressed in the inner ear and localize to inner
TRPV4 homomers are mechanosensitive when and outer hair cells as well as spiral ganglion
expressed in cultured cells and respond to hypo- cells. Behavioral and ABR threshold testing
osmotic stimuli, although this activation is show that deletion of TRPC3 or TRPC6 genes
slower than would be expected of a directly alone has no effect on hearing. However, when
gated mechanosensor. TRPV4 knockout mice both TRPC3 and TRPC6 are knocked out,
have normal hearing at 8 weeks of age, as shown high-frequency hearing is lost, as shown by
by ABR and distortion product otoacoustic ABR analysis and MET currents recorded
emission, suggesting that TRPV4 is not an es- from the basal, but not the apical, cochlear
sential component of the mechanotransduction hair cells are lost in vitro (Quick et al. 2012).
channel. However, at 24 weeks of age, these TRPC3/TRPC6 double-knockout mice have
mice exhibit increased ABR thresholds across hearing deficits at frequencies over 32 kHz,
all frequencies (Tabuchi et al. 2005). Compara- which corresponds with the ablation of MET
ble age-related hearing loss in humans has been currents in the basal, but not the apical,
mapped to the chromosomal region containing region of the cochlea from knockout animals
the human TRPV4 gene (Greene et al. 2001). (Figure 5).
No cell death or disruption of hair cells was Like TRP channels, TMC proteins are
found in TRPV4 knockout mice at either 8 or thought to have six transmembrane domains
24 weeks, and the mechanism of this delayed- and a pore loop. Functioning in a redundant
onset hearing loss is not known. TRPV4 manner, TMC1 and TMC2 loss have both been
mutations in humans cause an enormous vari- linked to deafness and hearing loss in humans
ety of disorders, including many developmental as well as mice (Kawashima et al. 2011). The
disorders as well as a neuropathy that can also similarities in structure and expression patterns
be associated with hearing loss. Conflicting (high levels in the cochlea and sensory neurons)
studies report the mutant TRPV4 to be either as well as the deafness associated with loss of
gain-of- (Deng et al. 2010) or loss-of-function TMC-1 all indicate that an interaction between
(Auer-Grumbach et al. 2010). However, as the TRP and TMC channels could contribute to
mutations are in the ankyrin repeat, domain mechanically sensitive channels in vivo.
disruption of protein-protein interactions
could be important (Zimon et al. 2010).
Gain-of-function mutations in TRPML3 CARDIOVASCULAR SYSTEM
found in the varitint-waddler mouse cause Within the cardiovascular system, various
deafness and vestibular dysfunction (van Aken mechanisms operate to sense changes in
et al. 2008). However, TRPML3 knockout metabolic demand and hemodynamics that are
mice have normal Preyer reflexes (ear flat- required to generate adequate responses to
tening in response to loud noise) and ABR maintain homeostasis. Transduction of me-
thresholds ( Jors et al. 2010). The hearing chanical forces such as shear stress, stretch, and
deficit is caused by stereocilia defects that arise (osmotic) pressure is key for the regulation of
because the mutant TRPML3 is constitutively vascular tone and local blood flow. Ca2+ signal-
active (Grimm et al. 2007). Similarly, TRPP1 ing is a central event in relaying these signals
is required for stereocilia structural integrity in the cardiovascular system. Endothelium and
but is not required for mechanotransduction vascular smooth muscle cells are involved in the
WT BC TRPC3/TRPC6 DKO AC
a DV b DV
1.5 1.5
Vm (mV) Vm (mV)
1.0 +96 1.0 +96
Current (nA)
Current (nA)
0.5 0.5
0 0
–164 –164
–0.5 –0.5
–1.0 –1.0
–1.5 –1.5
0 20 40 60 80 100 0 20 40 60 80 100
Time (ms) Time (ms)
I (nA)
c TRPC3/TRPC6 DKO BC d
DV
0.4
1.5
Vm (mV)
1.0 –160 –120 –80 –40

Current (nA)
+96
0.5
40 80
0 Vm (mV)
–164
–0.5 –0.4
–1.0
–1.5 –0.8
0 20 40 60 80 100
Time (ms)
WT BC (n = 4)
e WT (n = 8)
TRPC3/TRPC6 DKO AC (n = 5)
TRPC3/TRPC6 DKO BC (n = 8)
60 TRPC3/TRPC6 DKO (n = 9)
Threshold (dB)
40
***
**
20
5 6 7 8 9 20 30 40
Frequency (kHz)
Figure 5
Hearing loss and deficits in mechanotransduction in hair cells from TrpC3/C6 knockout mice. (a–c) MET
currents in response to 45 Hz sinusoidal force stimuli from a fluid jet in WT and TRPC3/TRPC6 outer hair
cells (OHCs). Holding potential was −84 mV, and the membrane potential was stepped in 20 mV
increments from −164 mV to +96 mV. Driver voltage (DV, amplitude 40 V) waveform to the fluid jet is
shown above the current traces. Positive DV moves the hair bundles in the excitatory direction toward the
kinocilium. Recordings in a–c are averages from two stimulus presentations each. (a) WT OHC, mid-basal
coil P2+1, Cm 5.6 pF; Rs 0.80 M. (b) TRPC3/TRPC6 DKO OHC, basal end of apical coil P2+2, Cm
7.4 pF; Rs 0.63 M. (c) TRPC3/TRPC6 DKO OHC, mid-basal coil P2+2, Cm 6.9 pF; Rs 0.74 M.
(d ) Current-voltage curves averaged from 4 WT OHCs from the basal coil, 5 apical-coil TRPC3/TRPC6
DKO OHCs and 8 basal-coil TRPC3/TRPC6 DKO OHCs. (e) Auditory brain stem recording (ABR)
response thresholds to tone bursts of wild-type (WT) (n = 8) and TRPC3/TRPC6 double knockout (DKO)
mice (n = 9). Data are expressed as mean ± SEM. ∗ , p < 0.05; ∗∗ , p < 0.01; ∗∗∗ , p < 0.001. AC, apical
cochlea; BC, basal cochlea; dB, decibel; nA, nanoAmps.
process of vascular mechanotransduction. Sub- acetylcholine-induced vasodilation is normal

stantial evidence exists that pressure or stretch (Hartmannsgruber et al. 2007). More recently,
induces membrane depolarization in blood ves- Matthews et al. (2010) showed that TRPV4 can
sels and the heart (Kuipers et al. 2012, Patel be activated by mechanical force via the relay
et al. 2010). Mechanically activated cation chan- of mechanical stretch through β1-integrin.
nels triggered by stretch or osmotic swelling A similar interplay between TRPV4 and
have been described in endothelial cells, vascu- α2β1-integrin has been found in mechan-
lar smooth muscle cells, and podocytes, which otransduction in the somatosensory system
are epithelial cells essential to plasma ultrafil- (Alessandri-Haber et al. 2008). Polycystins
tration (Inoue et al. 2009, Patel et al. 2010). (TRPP1, TRPP2) have a key role in renal and
The properties of these mechanically activated vascular mechanosensory transduction (Patel &
channels resemble those of TRP channels; they Honore 2010). In the primary cilium of renal,
are sensitive to blockage by Gd3+ and have nodal, and endothelial cells, polycystins may act
similar ion selectivity and conductance. Thus, as flow sensors (Patel & Honore 2010). More-
researchers have indicated that mechanosen- over, in arterial myocytes, the ratio of TRPP1
sitive TRP channels may play a role in car- and TRPP2 regulates pressure sensing (Sharif-
diovascular function. Several members of the Naeini et al. 2009). Polycystins also condition
TRP family, including TRPV, TRPC, TRPP, the stretch sensitivity of stretch-activated K2P
and TRPM, have been implicated in sensing channels in renal epithelial cells (Peyronnet
(osmo)mechanical stress ( Jin et al. 2011). et al. 2012). Although some research indicates
Multiple TRP members, including TRPC, that TRPC1 is intrinsically mechanosensitive
TRPA, TRPM, TRPV, and TRPP, have been (Maroto et al. 2005), this finding has been
identified in the heart and vasculature system disputed as CHO cells overexpressing TRPC1
(Inoue et al. 2009). Disturbed TRP channel do not show enhanced mechanosensitive
functioning has been associated with several currents (Gottlieb et al. 2008).
cardiovascular pathologies (Earley & Brayden Increasing evidence indicates that different
2010). TRP channels are also involved in regu- TRP channels interact and cooperate to form
lating the cellular function of endothelial cells. mechanosensitive complexes in the cardiovas-
Shear stress evokes an increase in intracellu- cular system. Heteromeric TRPV4-TRPC1
lar calcium in endothelial cells that provokes channels display distinct electrophysiological
the release of vasodilating agents such as ni- properties that differ from homomeric TRPV4
tric oxide that act on vascular smooth muscles. channels (Ma et al. 2011b). TRPC1 interacts
Although TRP channels in endothelial cells with TRPV4 to mediate shear-stress-induced
have been implicated in the detection of me- calcium influx in endothelial cells (Ma et al.
chanical stimuli such as shear stress, they are 2010). TRPV4 can also interact with other
also activated by vasoactive molecules (Kuipers members of the TRP family (see Table 1).
et al. 2012). However, a unitary inward cur- A common subunit arrangement may be
rent was identified by Lansman et al. (1987) present among heteromeric tetramers of TRP
that was associated with an increased opening channels, as TRPP2 and TRPV4 assemble
of a Ca2+ -permeable ion channel after the cell identically to TRPP2 and TRPC1 (Stewart
membrane patches of aortic endothelial cells et al. 2010). In blood-brain endothelial cells,
had been stretched. calcium influx induced by mechanical stretch
Endothelial TRPV4 is required for injury is probably mediated by TRPC1 and
shear-stress-induced vasodilation. Hypo- TRPP2 channels (Berrout et al. 2012b). Other
tonic cell-swelling-induced currents are also proteins are also likely involved in the modula-
lost in TRPV4−/− endothelial cells, and tion of TRP channel complexes in endothelial
TRPV4−/− mice show complete absence of function. For example, the protein Orai1, which
shear-stress-induced vasodilation, although spans four transmembrane domains, interacts
Table 1 TRP channels and mechanosensation

NE36CH23-Wood
Subfamily and Mechanosensitive

Species channel Mechanosensitivity complexes Cell type Reference(s)
ARI
Worms TRPV OSM-9 Touch, osmolarity, auditory Deg1 Neurons Liedtke (2007a), Geffeney
et al. (2011)
OCR-2 Touch, osmolarity Neurons Liedtke et al. (2000
TRPN TRP-4 Stretch Ciliated neurons Kang et al. (2010
26 May 2013
Flies TRPV NAN Auditory IAV Chordotonal organs Kim (2007)

IAV Auditory NAN Chordotonal organs Kim et al. (2003)
TRPN NOMPC Auditory Chordotonal neurons Effertz et al. (2011)
10:25
Yeast TRPY1 Osmolarity, stretch Vacuolar membrane Zhou et al. (2005), Denis &
Cyert (2002)
Zebrafish TRPM TRPM7 Touch Sensory neurons Low et al. (2011)
Mammals TRPV TRPV1 Stretch, osmolarity? Urothelial cells, colon Ciura & Bourque (2006),
afferent fibers Sharif et al. (2006)
TRPV2 Stretch, osmolarity? Epithelial cells, sensory Muraki et al. (2003)
neurons, smooth muscle
cells
TRPV4 Noxious pressure, shear stress, TRPP2, TRPC1, Sensory neurons, Wu et al. (2007)
osmolarity, stretch β1-integrin endothelial cells
TRPC TRPC1 Stretch, osmolarity, shear stress, TRPP2, TRPV4, Endothelial cells, sensory Chen & Barritt (2003),
touch TRPC4 neurons Maroto et al. (2005)
TRPC3 Touch, auditory TRPC6 Sensory neurons Quick et al. (2012)
TRPC5 Pressure, osmolarity Sensory neurons? Gomis et al. (2008)
TRCP6 Pressure, osmolarity, touch, TRPC3, Gq receptors Sensory neurons, cardiac Quick et al. (2012), Inoue
auditory (AT1R) myocytes, smooth et al. (2009), Spassova et al.
muscle cells (2006)
TRPP TRPP1 Pressure, shear stress TRPP2 Epithelial cells Nauli et al. (2003)
TRPP2 Pressure, shear stress TRPC1, TRPP1, Epithelial and endothelial Nauli et al. (2003)
TRPV4 cells
www.annualreviews.org • TRP Channels and Mechanosensation
TRPP3 Osmolarity Shimizu et al. (2009)
TRPA TRPA1 Pressure, stretch, osmolarity TRPV1 Sensory neurons Zhang et al. (2008)
529
TRPM TRPM3 Osmolarity Grimm et al. (2003)
TRPM4 Shear stress, stretch Smooth muscle cells Morita et al. (2007)
TRPM7 Stretch, osmolarity, shear stress Smooth muscle cells Numata et al. (2007a)
with the TRPC4/TRPC1 channel complex, and TRPC6 in a sensory neuron line confers
where it controls activation and channel- low-threshold mechanosensitivity (Quick et al.
permeation characteristics (Cioffi et al. 2012). 2012). However, another study found no ev-
The calcium sensor STIM1 also interacts with idence that Gq/11 -coupled receptor activation
TRPC channels and may be involved in the enhances the mechanosensitivity of TRPC-like
gating of these channels (Yuan et al. 2009). currents or the myogenic responsiveness of
Finally, the interaction with cytoskeletal pro- anterior cerebral arteries (Anfinogenova et al.
teins or extracellular matrix proteins through 2011). These differences may be inherently due
molecules such as integrins may be essential to to the fact that activity of the TRP-like chan-
tune the mechanosensitivity of TRPs. nels depends on cell-dependent machinery.
Smooth muscle TRP channels are impli- Indeed, TRP channel behavior is expression
cated in the transduction of changes in pressure system dependent (Lev et al. 2012). TRPM7
to changes in the vascular smooth muscle con- may be a stretch- and swelling-activated chan-
tractility of the cytoskeleton (Di & Malik 2010, nel. TRPM7 translocates to the membrane
Earley & Brayden 2010). Smooth muscle cells after shear stress that is associated with an
respond to changes in intraluminar pressure increase in native TRPM7 current amplitude

(termed the myogenic response). They are in smooth muscle cells (Oancea et al. 2006).
also affected by dilation in response to reduced In excised patches, TRPM7 displays single
intraluminar pressure and constriction in channel activity that is induced after membrane
response to increases in intraluminar pressure. stretch (Numata et al. 2007a).
Vascular smooth muscle cells express multiple
subunits of TRPs (Guibert et al. 2011), among
which TRPC6, TRPV2, and TRPM4 exhibit KIDNEY
some mechanosensitivity and, thus, could MECHANOTRANSDUCTION
participate in pressure-induced depolarization All subfamilies of the TRP channels are ex-
(Kuipers et al. 2012). TRPV2 is a component pressed in the kidney, and several play a role
of an osmo(mechanical)-sensitive channel. in multiple kidney disorders (Hsu et al. 2007).
TRPV2 expression in CHO cells induces Although TRP channels regulate many differ-
swelling-activated currents with similar char- ent functions in the kidney, sensing mechan-
acteristics to the endogenous channel in aortic ical cues is an important function for normal
smooth muscle cells that is activated by osmotic renal function. Podocytes, the epithelial cells
changes (Muraki et al. 2003). TRPC6 antisense in the kidney, play an important role in ul-
oligonucleotides reduce the expression of trafiltration of plasma. They are exposed and
TRPC6 in smooth muscle cells and attenuate sense different forms of mechanical stimuli,
hypo-osmotic-induced cation currents (Welsh including mechanical stress due to glomeru-
et al. 2002). Overexpression of TRPC6 alone lar capillary pressure, shear stress, and changes
does not induce mechanosensitivity in different in osmolarity. Podocytes react and adapt to
cell lines (Quick et al. 2012, Yin & Kuebler these mechanical cues via cytoskeletal rear-
2010). However, TRPC6 mechanosensitivity rangements to maintain the glomerular bar-
has been linked to Gq/11 -coupled receptors rier (Greka & Mundel 2012). TRPV4 mediates
(Inoue et al. 2009, Schnitzler et al. 2008, hypotonic cell-swelling-induced calcium influx
Sharif-Naeini et al. 2010). In cardiac myocytes, (reviewed in Pedersen et al. 2011). Some re-
mechanical stress can activate TRPC channels ports showed that osmosensitivity of TRPV4
indirectly through the angiotensin II type 1 re- is mediated through archidonic acid metabo-
ceptor (AT1R) (Dietrich et al. 2005, Schnitzler lite 5 , 6 -epoxyeicosatrienoic acid (Nilius et al.
et al. 2008). Whereas coexpression of AT1R 2004). However, in yeast that do not synthe-
with TRPC6 in HEK293 cells does not confer size the metabolite, TRPV4 still responds to
mechanosensitivity, coexpression of TRPC3 changes in osmolarity (Loukin et al. 2009). The
precise mechanisms that underpin osmosen- to be mechanically gated, TRPV1-deficient

sitivity of TRPV4 remain unclear, although mice display reduced mechanosensitivity of the
TRPV4 function dependents on cytoskeletal el- bladder and urothelial cells display diminished
ements and can also interact with aquaporin- hypoosmolarity-evoked ATP and NO release
5 (Liu et al. 2006). Mutations in the PDK1 (Birder et al. 2002, Daly et al. 2007).
and PDK2 genes encoding TRPP1 and TRPP2 TRPV4 is highly expressed in bladder
are the major cause of autosomal-dominant epithelium and in sensory neurons innervating
polycystic kidney disease. As mentioned above, the colon (Araki 2011, Brierley et al. 2008).
TRPP1 and TRPP2 from the polycystin family Stretch-evoked Ca2+ influx is decreased in
could function as mechanosensors in renal ep- urothelial cells from TRPV4-deficient mice
ithelial cells (Patel & Honore 2010). Recently, (Mochizuki et al. 2009), and a TRPV4 agonist
Wang et al. (2012) showed that the actin cross- induces bladder contraction and overreactivity
linking protein filamin regulates TRPP2 func- (Thorneloe et al. 2008). In the colon, TRPV4
tion. Podocyte injury is characterized by dereg- contributes to mechanically evoked visceral
ulated calcium homeostasis (Hunt et al. 2005), pain (Brierley et al. 2008). TRPV2 is expressed
and TRPC6 has been linked to human genetic in nerve fibers within the muscularis and
kidney disease (Reiser et al. 2005, Winn et al. myenteric plexus, myenteric cell bodies, as well
2005). To regulate AT1R-mediated cytoskele- as epithelial cells in the stomach and intestine
tal remodeling, TRPC5 and TRPC6 function (Kashiba et al. 2004, Kowase et al. 2002, Zhang
in a protein complex with Rac and RhoA (Rho et al. 2004). In urothelial cells, TRPV2 is
family of small guanosine triphosphatases), re- expressed and activation of TRPV2 induces
spectively (Tian et al. 2010). Finally, TRPM7 a Ca2+ flux (Everaerts et al. 2010). Although
produces osmotic swelling and pressure- TRPV2 may mediate stretch-induced calcium
induced currents (Numata et al. 2007a). influx (Muraki et al. 2003), a role for TRPV2 in
visceral organ mechanosensation has not been
explored.
VISCERAL
MECHANOSENSATION
Mechanosensation in the bladder or intestinal TRP INTERACTIONS WITH
tract can occur directly through activation OTHER PROTEINS AND
of afferent nerve fibers or indirectly through MECHANOTRANSDUCTION
mediators released by from non-neuronal The bewildering variety of TRP channel
cells that act through afferent fibers. Some protein interactions has been comprehensively
evidence suggests that TRP channels also play cataloged by the TRIP (Mammalian Tran-
a role in mechanosensation in viscera. TRPM8 sient Receptor Potential Channel-Interacting
is detected in a small portion of primary Protein) Database (Shin et al. 2011). As an
sensory neurons that innervate the bladder example, we have selected the topic of inter-
(Hayashi et al. 2009) and colon (Harrington actions between TRPC3 and proteins involved
et al. 2011). Icilin, a TRPM8 superagonist, in mechanotransduction because of the po-
desensitizes colon afferent to mechanical stim- tential role of TRPC3 in somatosensation and
ulation and may couple to TRPV1 and TRPA1 hearing. Peer-reviewed papers from 1997 to
to inhibit their downstream chemosensory and 2012 show 58 interactions have been validated
mechanosensory actions (Harrington et al. in vivo and/or in vitro studies. Interactions
2011). The behavioral responses to noxious were determined via coimmunoprecipitation,
colonic distension are reduced in TRPA1−/− patch clamp electrophysiology, fusion protein
mice, suggesting that TRPA1 is required for pull-down assay, calcium measurement, coim-
normal visceral mechanosensation (Brierley munofluorescence staining, fluorescence probe
et al. 2009). Although TRPV1 is not considered labeling, FRET, yeast two-hybrid screens, in
Calreticulin
Calreticu
C lr tiic i SNAP23
SNAP
A 23
Gq/11
Gq//11 AQP-2
AQP
AQP2
NCX1 IP3R2
P3R2
STIM2
ST 2
Caveolin-1
Cav
Caveolin-
C av
veolin
v eoli
o n1
Epo-R TRPC5
TRPC5
TRPC
PDE3A
PDE3
D A
PLC2 MG29 IP3R1
P3R1
Ezrin
zri
CaSR
IP3R3
P3R3
BKca
Kc
T C77
TRPC7 Orai1
Or i1
PMCA
A
GC-A
A
PLC3
PLC1
Junctophilin-2
J ctoph
p ii 2
F KBP12
K
FKBP122 PLC1
Or i3
Orai3 TrkB
Trk
GLUT
GLUT-4
T4 TRPC3
PKC
C
VAMP2
V M 2
VA
VAMP WNK4
WNK
WNK44
NKA1
Orai2
Or i2
MxA
A
SNAP SRC
PKG1
PK 1 Homer
PKA
A
RyR RACK1
1
TRPM4
T M4
RyR2
2
STIM1
Sy
S yntaxin
t i 3
tax
Syntaxin3 TRPC4
T RPC4 PLC2
TRPC SERCA2
TRPC1 S RCA
A2 TRPP1
T RPP TRPC6
TRPC
T C6
TRP channels Calmodulin
C lmod
od
d li
RNF24
N H
Hoomerr 1
Homer-1 JJunctate
unctat
ct
Mechanotransduction C av1.
v1.2
Cav1.2
proteins
Figure 6
Protein-protein interactions of TRPC3. Protein-protein interactions of TRPC3 with cellular proteins taken
from the TRIP (Mammalian Transient receptor potential channel-interacting Protein) Database
(http://www.tripdatabase.com). Green circles indicate TRP channels; yellow circles indicate proteins
implicated in mechanotransduction.
vitro post-translational modification assay, or mice, an increased cation influx can be blocked
cell surface biotinylation assays using human, by GsMtx4, a known stretch-activated channel
mouse, rat, or bovine TRPC3 constructs blocker (Stiber et al. 2008).
(see Figure 6). Phospholipases coimmunoprecipitated with
Aquaporins (AQP) have been implicated in TRPC3 in epithelial cells (Bandyopadhyay et al.
hearing (Li & Verkman 2001) and are found 2005) and HEK cells (Tong et al. 2008). Phos-
in specialized mechanosensitive cells in hu- pholipases are activated by stretch in Xeno-
man skin (Nandasena et al. 2007). AQP2 coim- pus oocytes (Montag et al. 2004), cardiomy-
munoprecipitates with TRPC3 in rat kidney ocytes (Ruwhof et al. 2001), and aortic tissue
cells (Goel et al. 2007) and is required for (Matsumoto et al. 1997). Additionally, when
calcium influx in response to hypotonic shock phospholipase C (PLC) β2 is knocked down
(Galizia et al. 2008). Homer-1 coimmunopre- in cultured osteoblasts, responses to fluid shear
cipitates with TRPC3 in HEK cells and regu- stress are diminished (Hoberg et al. 2005).
lates plasma membrane translocation of chan- These enzymes may produce lipid activators of
nels (Kim et al. 2006). In Homer-1 knockout mechanosensitive TRPs.
STIM and Orai proteins are also important These examples underline the potential
in regulating calcium entry. They interact with diversity of TRP-dependent interactions that
a number of TRPs including TRPC3, as shown may play a role in mechanotransduction.
by coimmunoprecipitation in HEK cells and Physical interactions may also define the
platelets (Berna-Erro et al. 2012, Liao et al. cellular environment in which TRP channels
2007). Orai1 plays a role in stretch sensing in can function in mechanotransducing com-
cardiomyocytes: siRNA knockdown for Orai1 plexes. Although neither TRPC3 nor TRPC6
impairs stretch-mediated responses (Volkers expressed in HEK293 or CHO cells responds
et al. 2012). In various systems, cytoskeletal in- to mechanical pressure, rapidly adapting
teractions have also been implicated in mechan- mechanosensitive currents are expressed in the
otransduction. Ezrin is a protein that serves as neuronal cell line ND-C, expressing TRPC3
an intermediate between the plasma membrane channels, which is potentiated by coexpression
and the cytoskeleton and interacts with TRPC3 of TRPC6 (Quick et al. 2012) (Figure 7). Addi-
(Lockwich et al. 2001). Ezrin also interacts tional proteins in the ND-C cell line that traffic
with the mechanosensitive channel TREK-1 or contribute to mechanosensitive channels

(Lauritzen et al. 2005). may explain the cell-type-specific expression of
HEK 293 cells CHO K1

a Displacement (μm) b Displacement (μm)
0 1.3 2.6 3.9 5.2 6.5 7.8 0 1.3 2.6 3.9 5.2 6.5
0
–50
I (pA)
–100
–150
Empty vector (n = 9) Empty vector (n = 9)
TRPC3/TRPC6 (n = 9) TRPC3/TRPC6 (n = 9)
–200
ND-C cells
c Displacement (μm)
9.9 (μm)
0 1.8 3.6 5.4 7.2 9.0

0 d
0
**
***
*** –50
–50
***
I (pA)
***
***
–100
I (pA)
–100 Empty vector

*** TRPC3/TRPC6
–150
***
TRPC3
TRPC6
–150 Empty vector (n = 33)
–200
TRPC3/TRPC6 (n = 11) 0 100 200 300 400 500
TRPC3 (n = 12)
Time (ms)
TRPC6 (n = 13)
–200
Figure 7
Heterologous expression of TRPC3 with or without TRPC6 confers mechanosensitivity on some cell lines.
TRPC3 and TRPC6 alone or together do not confer mechanosensitivity on HEK 293 or CHO cells.
Mechanical distension of the neuronal ND-C cell line expressing TRPC3 or TRPC3, and TRPC6 produces
large rapidly adapting currents shown in panel d from Quick et al. 2012.
mechanosensitivity of TRPC3. The lipid en- (Muraki et al. 2003). Cardiomyocytes exposed
vironment in which the channels are expressed to hypotonic solutions induce cationic currents
may also play an important role in channel that can be blocked by PLC inhibition or AT1R
gating mechanisms (Carrillo et al. 2012). blockade, and they are not present in TRPC1−/−
mice (Seth et al. 2009). Hypo-osmotic ac-
tivation of TRPC5 appears to depend on
TRP CHANNEL GATING phosphatidylinositol 4,5-bisphosphate (PIP2 )
MECHANISMS levels. PIP2 -depleted cells show low levels of
Activation of mechanotransduction channels by activation that can be rescued by the addition of
membrane perturbation phospholipids or lipid exogenous PIP2 . Temperature also plays a part
second messengers released by phospholipases in the sensation of hypertonic stimuli: TRPV1-
have been investigated as potential mechanisms transfected HEK293 cells show minimal
and are summarized below. response to hypertonic solutions at 24◦ C but
a robust increase of Ca2+ at 36◦ C (Nishihara
et al. 2011). TRPV4 can be activated by shear

Membrane Perturbation and Potential stress generated by fluid flow when transfected
Direct Activation into HEK cells (Mendoza et al. 2010, Wu et al.
The sensitivity of TRP channels in response 2007). TRPM7 expressed in HEK cells or
to membrane tension has been investigated found endogenously in HeLa cells can also be
in heterologous expression systems. TRPV2 activated by fluid flow (Numata et al. 2007a,b).
expressed in CHO cells grown on an elastic Endogenously expressed TRP channels
membrane can be activated by membrane also show activation by membrane tension. In
stretch and by pressure applied with a patch mouse kidney tissue, shear-stress flow induces
pipette (Muraki et al. 2003). Mammalian a sustained rise in Ca2+ that is abolished in
TRPA1 does not form a mechanically activated TRPV4−/− animals (Berrout et al. 2012a).
channel when transfected into mammalian cells TRPP1 is also implicated in fluid flow sensing,
(Rugiero & Wood 2009), but C. elegans TRPA1 as mutations in TRPP1 result in abolition
expressed in CHO cells can be activated by of fluid flow–induced Ca2+ rises in cultured
50 mm Hg suction in patch-clamp experiments kidney epithelial cells (Nauli et al. 2003).
(Kindt et al. 2007). TRPV4 can also be activated Brain endothelial cells grown on an elastic
by suction when expressed in Xenopus oocytes membrane exhibit an influx of Ca2+ when a
(Loukin et al. 2009). TRPM4 and TRPM7 50-ms stretching pulse is applied. This current
in HEK cells can be activated by negative is decreased when TRPP2 and TRPC1 are
pressure of approximately 20 mm Hg (Morita knocked down by siRNA (Berrout et al. 2012b).
et al. 2007, Numata et al. 2007a), and TRPC5 Similarly, stretch-activated Ca2+ increases in
in HEK2983 cells can be activated by positive myoblasts show a 90% reduction after knock-
pressure of approximately 21.3 mm Hg (Gomis down of TRPC1 by siRNA (Formigli et al.
et al. 2008). Although disputed in different cell 2009). Mechanical stretch also activates en-
lines, TRPC6-expressing HEK cells can also be dogenous TRPC6 in cardiomyocytes, and
activated by negative pressure (Gottlieb et al. expression of dominant-negative TRPC6
2008, Quick et al. 2012, Spassova et al. 2006). strongly reduces the Ca2+ increase in response
TRPC5, TRPM3, and TRPV4 can be acti- to 20% transient stretch (Nishida et al. 2010).
vated by osmotic pressure when transfected into Nevertheless, all these examples of TRP
HEK cells (Fan et al. 2009; Grimm et al. 2003, activation could depend, not on membrane
2008). TRPV2 expressed in CHO cells as well deformation, but on the actions of second mes-
as endogenously expressed TRPV2 in myocytes sengers released from distinct mechanosensors
can also be activated by hypo-osmotic solutions (see Figure 8).
Indirect Activation been overviewed (Rohacs et al. 2008). The role

of other phospholipids has received little at-
Trafficking, second messengers, and posttrans-
tention. There is evidence for PLD activation
lational modification are potential mechanisms
of TRPC3 downstream of metabotropic gluta-
of TRP channel regulation (Figure 9). Calcium
mate receptor activation and translocation of
homeostasis involving store-activated channel
the enzyme to the membrane. PLD releases
activity as well as STIM and Orai may con-
phosphatidic acid and choline and may sub-
tribute to TRP channel trafficking. They also
sequently produce lysophosphatidic acid and
enhance calcium fluxes, and mechanical cur-
diacylglycerol (DAG) (Glitsch 2010). Intrigu-
rents in some cells seem to depend on this pro-
ingly, TRPC3-mediated calcium fluxes evoked
cess (e.g., Volkers et al. 2012).
by DAG in T cells depend on the fatty acid at
Second-messenger activation of TRP
the 2 position of DAG. Thus, DAG-containing
channels does not involve cyclic nucleotides,
oleic acid is an effective agonist, whereas arachi-
but a variety of lipid second messengers
donic acid at the 2 position is much less ef-
are effective agonists, raising the possibility
fective (Carrillo et al. 2012). Sphingosine-1-

that TRP channels are not directly gated

phosphate is a product of ceramidase that acts
by mechanical force in vivo but instead are
through the GPCR SP1R1 and has been im-
activated downstream of uncharacterized
plicated in the gating of TRPC1 channels that
mechanosensors (Makino et al. 2006). All seven
are repeatedly associated with mechanosensa-
families of the TRP channels contain members
tion (Formigli et al. 2009).
that can be activated by PLC-coupled GPCR
Most studies of lipid activation of TRP
receptors and downstream signaling cascades.
channels have focused on inositol phospholipid
The possibility of mechanosensation being
derivatives because the function of these second
downstream of a GPCR has been extensively
messengers in intracellular calcium signaling is
explored with the AT1R implicated in the
well known. PLC activation leads to the hydrol-
myogenic response (Storch et al. 2012b).
ysis of PIP2 -releasing DAG, inositol triphos-
Evidence that agonist activation of the AT1R is
phate (IP3 ), which releases both calcium and
mimicked by agonist-independent mechanical
protons from intracellular stores, as emphasized
stress on the membrane has been presented.
in recent studies of Drosophila TRP channels.
However, coexpression of AT1R with TRPC6
For example, Huang et al. (2010) found that
does not confer mechanical sensitivity in a
PIP2 hydrolysis and intracellular acidification
number of cell lines (e.g., Quick et al. 2012).
activated TRPL channels. Early work showed
Thus, this mechanism may not represent a
that polyunsaturated fatty acids (PUFAs) were
general model for channel activation.
also channel activators (Chyb et al. 1999).
If GPCRs and lipids are required for
However, Lev et al. 2012 observed no activa-
mechanosensation by TRP channels, which
tion of TRPL channels with PIP2 hydrolysis
second messengers are involved? Lipid regu-
and intracellular acidification in transfected
lation of TRP channel activity has been de-
HEK cells (Lev et al. 2012). Yet, PUFAs do ac-
scribed in many systems (e.g., Kahn-Kirby et al.
tivate the channel, and inhibitors of DAG lipase
2004). Studies of the lipid activation of TRP
could block this effect—another example of dif-
channels have focused on inositol phospholipid
ferent observations in distinct cellular contexts.
derivatives and PLC because of their important
PUFAs that activate TRP channels are likely
roles in regulating intracellular calcium lev-
to be produced by DAG lipases downstream
els. PIP2 has been proposed to block TRPV1,
of PLC or by PLA2 activation. In C. elegans,
with PLC-mediated hydrolysis releasing the in-
a subset of PUFAs with omega-3 and omega-6
hibition. However, PIP2 activates TRPV1 in
acyl groups acts as endogenous modulators
isolated patches. The mechanisms involved in
of TRPV signal transduction (Kahn-Kirby
these two apparently contradictory events have
et al. 2004). Motter & Ahern (2012) also found
potent agonist effects of PUFAs on mammalian depletion of IP3 catalyzed by PLC leaving
TRPA1. DAG in the membrane can cause photore-
A recent study potentially reconciles the ceptor contraction that may be the result of
membrane deformation/second messenger altered membrane tension that is visible at the
debate on TRP mechanotransduction by pro- light-microscope level. Hypo-osmotic tension
viding compelling evidence that light sensing causing membrane deformation also results in
in Drosophila is directly mediated by membrane increased TRP channel activity. Gramicidin,
tension–mediated mechanical activation of a cation selective mechanosensitive channel,
TRP channels (Hardie & Franze 2012). The shows enhanced channel activity when light
Positive Cell swelling Shear stress

pressure Crenato
r
a
Direct
activation
TRP
er
channel Cup form
b
Second
messenger
PIP2
PLC
DAG
IP3
IP3R
Dual tether Single tether
c
Extracellular
matrix
interaction
Physical interactions
of phospholipids
Charge interactions of phospholipids
d
Bilayer
composition +
- - -
+ + +
+ +
+
M e ch a n ica l s t i m u l a t i o n
Na/Ca
TRPC3
TRPC1
PUFA
DAG
Integrins PIP2
Membrane
P
distension
P
Cytoskeleton Homer PLC
P
Ca2+
P
IP3 β
γ
GPCR
P
IP3R α
STIM-1
ER
Figure 9
Mechanisms of mechanosensitive TRP activation. Intracellular proteins STIM and Homer have been linked
to TRPC1 trafficking and activation. TRPC1 is known to require other TRP channels to function at the
membrane. Membrane distension may itself activate the channels, whereas various lipids, particularly
PUFAs, and the release of IP3 from PIP2 may alter membrane tension and activate TRPs in a way that is
similar to the Drosophila visual system. Abbreviations: DAG, diacylglycerol; ER, endoplasmic reticulum;
GPCR, g protein–coupled receptor; IP3 , inositol trisphosphate; PIP2 , phosphatidylinositol
4,5-bisphosphate; PLC, phospholipase C; PUFA, polyunsaturated fatty acids.
stimulates photoreceptors, clearly demon- heat sensing in Drosophila (Fowler & Montell
strating that light acting via rhodopsin causes 2013). In the Hardie scheme, PLC acts to
membrane deformation. This has interesting alter membrane structure through the release
implications for the role of rhodopsins in of IP3 . DAG-derived negatively charged
←−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−
Figure 8
Mechanisms for activating TRP channels. (a) Direct activation. Positive pressure or hypo-osmolarity cause the membrane to curve
inward; this action can be replicated by cup formers, which insert into the inner leaflet of the bilayer, and also by cone-shaped lipids or
lipids with large head groups. The opposite membrane curvature can be achieved by hyperosmotic cell swelling or application of
crenators, which insert into the outer leaflet of the membrane. Shear stress occurs in tissues such as blood vessels and bone from fluid
flow or friction; the membrane is put under stress by the movement and changes shape. (b) Second messengers. The ion channel may be
activated indirectly by second-messenger signaling cascades from closely associated G protein–coupled receptors (GPCRs). GPCRs
activate phospholipase C (PLC) leading to hydrolysis of PIP2 to form diacylglycerol (DAG), which could activate the channel directly,
and inositol triphosphate (IP3 ), which could activate the channel via IP3 R. (c) Extracellular matrix interaction. The dual tether model is
proposed for vertebrate hair cell transduction. Intra- and extracellular tethers transfer the mechanical force to the channel to enable
channel opening. The single tether model employs the same principle of mechanical forces being transferred to the channel but with
just intra- or extracellular tethers. (d ) Bilayer composition. The composition of the bilayer has a huge effect on the shape and structure
of the membrane and its interactions with membrane proteins. Hypothetical models include those that utilize charge interactions
between phospholipids and ion channels, mechanical force causing phosphorylation or hydrolysis of charged phospholipids; the
modified lipid loses the charges, severing interactions and enabling the channel to change conformation and open. This principle could
also work in reverse, with charged interactions favoring the open conformation of the channel. Alternatively, the modification of the
lipids could simply exert membrane curvature by a difference in head group shape and the membrane curvature directly opening the
channel, as in panel a.
PUFAs acting through the outer leaflet of in TRPV4 also suggests that many functions of
the membrane could also enhance membrane TRP channels remain unidentified (Cho et al.
tension. The use of gramicidin as a probe 2012). TRPV4 and TRPML3 knockouts are
combined with studies of TRP channels relatively normal, whereas gain-of-function
to examine the effects of lipid mediators mutants have dramatic phenotypes, suggesting
on membrane-mediated channel openings that redundancy in TRP function masks some
should be applicable to other mechanosensory functions of TRP channels are not detected in
systems. knockout mice.
Recent advances in the understanding of
Drosophila visual transduction have provided
FUTURE PROSPECTS strong evidence that membrane perturbation
The diversity of the physiological roles of in rhabdomere microvilli caused by PLC
TRP channels and their structural complexity activity can directly activate the prototypical
help explain some of the discrepancies in TRP channel (Hardie & Franze 2012). This
experimental observations made in vitro on the dramatic observation, if translated into mam-
mechanisms associated with the gating of these malian systems, could explain the multiple
channels. The multiple roles of TRP channels effects of many lipid second messengers on
also suggests that exploiting them as drug mechanotransduction in terms of their ability
targets will be a daunting task. For example, to perturb membrane structure and indirectly
mammalian TRPA1 has been implicated not gate TRP channels. Thus, the case for some
only in sensing environmental hazards, cold, TRP channels being direct mechanotransduc-
and mechanical pressure, but also in regulating ers is becoming more convincing; unraveling
inhibitory synapse activity through the effects the mechanisms through which lipids regulate
of astrocyte intracellular calcium (Shigetomi TRP channel activity is likely to give new
et al. 2012). The vast range of human develop- insights into mechanotransduction as well as
mental disorders linked to different mutations other forms of sensation.
DISCLOSURE STATEMENT
The authors are not aware of any affiliations, memberships, funding, or financial holdings that
might be perceived as affecting the objectivity of this review.
ACKNOWLEDGMENTS
We thank the BBSRC, the MRC, and the Wellcome Trust for generous support. J.N.W. was also
supported by WCU grant R31-2008-000-10103-0 at SNU. We apologize for omissions caused
by space constraints or oversights and thank many colleagues for helpful comments. N.E. was
supported by a Rubicon fellowship of the Netherlands Organisation for Scientific Research.
LITERATURE CITED
Alessandri-Haber N, Dina OA, Joseph EK, Reichling DB, Levine JD. 2008. Interaction of transient receptor
potential vanilloid 4, integrin, and SRC tyrosine kinase in mechanical hyperalgesia. J. Neurosci. 28:1046–
57
Amato V, Vina E, Calavia MG, Guerrera MC, Laura R, et al. 2012. TRPV4 in the sensory organs of adult
zebrafish. Microsc. Res. Tech. 75:89–96
Andersson DA, Gentry C, Moss S, Bevan S. 2009. Clioquinol and pyrithione activate TRPA1 by increasing
intracellular Zn2+ . Proc. Natl. Acad. Sci. USA 106:8374–79
Anfinogenova Y, Brett SE, Walsh MP, Harraz OF, Welsh DG. 2011. Do TRPC-like currents and G protein-
coupled receptors interact to facilitate myogenic tone development? Am. J. Physiol. Heart. Circ. Physiol.
301:H1378–88
Araki I. 2011. TRP channels in urinary bladder mechanosensation. Adv. Exp. Med. Biol. 704:861–79
Auer-Grumbach M, Olschewski A, Papic L, Kremer H, McEntagart ME, et al. 2010. Alterations in the
ankyrin domain of TRPV4 cause congenital distal SMA, scapuloperoneal SMA and HMSN2C. Nat.
Genet. 42:160–64
Bandyopadhyay BC, Swaim WD, Liu X, Redman RS, Patterson RL, Ambudkar IS. 2005. Apical localization
of a functional TRPC3/TRPC6-Ca2+ -signaling complex in polarized epithelial cells. Role in apical Ca2+
influx. J. Biol. Chem. 280:12908–16
Berna-Erro A, Galan C, Dionisio N, Gomez LJ, Salido GM, Rosado JA. 2012. Capacitative and non-
capacitative signaling complexes in human platelets. Biochim. Biophys. Acta 1823:1242–51
Berrout J, Jin M, Mamenko M, Zaika O, Pochynyuk O, O’Neil RG. 2012a. Function of transient receptor
potential cation channel subfamily V member 4 (TRPV4) as a mechanical transducer in flow-sensitive
segments of renal collecting duct system. J. Biol. Chem. 287:8782–91
Berrout J, Jin M, O’Neil RG. 2012b. Critical role of TRPP2 and TRPC1 channels in stretch-induced injury
of blood-brain barrier endothelial cells. Brain Res. 1436:1–12

Beurg M, Evans MG, Hackney CM, Fettiplace R. 2006. A large-conductance calcium-selective mechanotrans-
ducer channel in mammalian cochlear hair cells. J. Neurosci. 26:10992–1000
Birder LA, Nakamura Y, Kiss S, Nealen ML, Barrick S, et al. 2002. Altered urinary bladder function in mice
lacking the vanilloid receptor TRPV1. Nat. Neurosci. 5:856–60
Brierley SM, Castro J, Harrington AM, Hughes PA, Page AJ, et al. 2011. TRPA1 contributes to specific
mechanically activated currents and sensory neuron mechanical hypersensitivity. J. Physiol. 589:3575–93
Brierley SM, Hughes PA, Page AJ, Kwan KY, Martin CM, et al. 2009. The ion channel TRPA1 is required
for normal mechanosensation and is modulated by algesic stimuli. Gastroenterology 137:2084–95
Brierley SM, Page AJ, Hughes PA, Adam B, Liebregts T, et al. 2008. Selective role for TRPV4 ion channels
in visceral sensory pathways. Gastroenterology 134:2059–69
Carrillo C, Hichami A, Andreoletti P, Cherkaoui-Malki M, Del Mar CM, et al. 2012. Diacylglycerol-
containing oleic acid induces increases in [Ca2+ ]i via TRPC3/6 channels in human T-cells. Biochim.
Biophys. Acta 1821:618–26
Chen J, Barritt GJ. 2003. Evidence that TRPC1 (transient receptor potential canonical 1) forms a Ca2+ -
permeable channel linked to the regulation of cell volume in liver cells obtained using small interfering
RNA targeted against TRPC1. Biochem. J. 373:327–36
Cho TJ, Matsumoto K, Fano V, Dai J, Kim OH, et al. 2012. TRPV4-pathy manifesting both skeletal dysplasia
and peripheral neuropathy: a report of three patients. Am. J. Med. Genet. A 158A:795–802
Chyb S, Raghu P, Hardie RC. 1999. Polyunsaturated fatty acids activate the Drosophila light-sensitive channels
TRP and TRPL. Nature 397:255–59
Cioffi DL, Wu S, Chen H, Alexeyev M, St Croix CM, et al. 2012. Orai1 determines calcium selectivity of an
endogenous TRPC heterotetramer channel. Circ. Res. 110:1435–44
Ciura S, Bourque CW. 2006. Transient receptor potential vanilloid 1 is required for intrinsic osmoreception
in organum vasculosum lamina terminalis neurons and for normal thirst responses to systemic hyperos-
molality. J. Neurosci. 26:9069–75
Corey DP, Hudspeth AJ. 1983. Kinetics of the receptor current in bullfrog saccular hair cells. J. Neurosci.
3:962–76
Cosens DJ, Manning A. 1969. Abnormal electroretinogram from a Drosophila mutant. Nature 224:285–87
Coste B, Xiao B, Santos JS, Syeda R, Grandl J, et al. 2012. Piezo proteins are pore-forming subunits of
mechanically activated channels. Nature 483:176–81
Daly D, Rong W, Chess-Williams R, Chapple C, Grundy D. 2007. Bladder afferent sensitivity in wild-type
and TRPV1 knockout mice. J. Physiol. 583:663–74
Delmas P, Hao J, Rodat-Despoix L. 2011. Molecular mechanisms of mechanotransduction in mammalian
sensory neurons. Nat. Rev. Neurosci. 12:139–53
Deng HX, Klein CJ, Yan J, Shi Y, Wu Y, et al. 2010. Scapuloperoneal spinal muscular atrophy and CMT2C
are allelic disorders caused by alterations in TRPV4. Nat. Genet. 42:165–69
Denis V, Cyert MS. 2002. Internal Ca2+ release in yeast is triggered by hypertonic shock and mediated by a
TRP channel homologue. J. Cell Biol. 156:29–34
Di A, Malik AB. 2010. TRP channels and the control of vascular function. Curr. Opin. Pharmacol. 10:127–32
Dietrich A, Kalwa H, Rost BR, Gudermann T. 2005. The diacylgylcerol-sensitive TRPC3/6/7 subfamily of
cation channels: functional characterization and physiological relevance. Pflug. Arch. 451:72–80
Drew LJ, Rugiero F, Cesare P, Gale JE, Abrahamsen B, et al. 2007. High-threshold mechanosensitive ion
channels blocked by a novel conopeptide mediate pressure-evoked pain. PLoS ONE 2:e515
Drew LJ, Wood JN, Cesare P. 2002. Distinct mechanosensitive properties of capsaicin-sensitive and
-insensitive sensory neurons. J. Neurosci. 22:RC228
Dubin AE, Schmidt M, Mathur J, Petrus MJ, Xiao B, et al. 2012. Inflammatory signals enhance piezo2-
mediated mechanosensitive currents. Cell Rep. 2:511–17
Earley S, Brayden JE. 2010. Transient receptor potential channels and vascular function. Clin. Sci. 119:19–36
Effertz T, Wiek R, Gopfert MC. 2011. NompC TRP channel is essential for Drosophila sound receptor
function. Curr. Biol. 21:592–97
Eijkelkamp N, Linley JE, Torres JM, Bee L, Dickenson AH et al. 2013. A role for Piezo2 in EPAC1-dependent
mechanical allodynia. Nat. Commun. doi: 10.1038/ncomms2673

Everaerts W, Vriens J, Owsianik G, Appendino G, Voets T, et al. 2010. Functional characterization of transient
receptor potential channels in mouse urothelial cells. Am. J. Physiol. Renal. Physiol. 298:F692–701
Fan HC, Zhang X, McNaughton PA. 2009. Activation of the TRPV4 ion channel is enhanced by phosphor-
ylation. J. Biol. Chem. 284:27884–91
Farris HE, LeBlanc CL, Goswami J, Ricci AJ. 2004. Probing the pore of the auditory hair cell mechanotrans-
ducer channel in turtle. J. Physiol. 558:769–92
Formigli L, Sassoli C, Squecco R, Bini F, Martinesi M, et al. 2009. Regulation of transient receptor potential
canonical channel 1 (TRPC1) by sphingosine 1-phosphate in C2C12 myoblasts and its relevance for a
role of mechanotransduction in skeletal muscle differentiation. J. Cell Sci. 122:1322–33
Fowler MA, Montell C. 2013. Drosophila TRP channels and animal behavior. Life Sci. 92(8–9):394–403
Galizia L, Flamenco MP, Rivarola V, Capurro C, Ford P. 2008. Role of AQP2 in activation of calcium entry
by hypotonicity: implications in cell volume regulation. Am. J. Physiol. Renal. Physiol. 294:F582–90
Garrison SR, Dietrich A, Stucky CL. 2012. TRPC1 contributes to light-touch sensation and mechanical
responses in low-threshold cutaneous sensory neurons. J. Neurophysiol. 107:913–22
Geffeney SL, Cueva JG, Glauser DA, Doll JC, Lee TH, et al. 2011. DEG/ENaC but not TRP channels are
the major mechanoelectrical transduction channels in a C. elegans nociceptor. Neuron 71:845–57
Glitsch MD. 2010. Activation of native TRPC3 cation channels by phospholipase D. FASEB J. 24:318–25
Goel M, Sinkins WG, Zuo CD, Hopfer U, Schilling WP. 2007. Vasopressin-induced membrane trafficking
of TRPC3 and AQP2 channels in cells of the rat renal collecting duct. Am. J. Physiol. Renal. Physiol.
293:F1476–88
Gomis A, Soriano S, Belmonte C, Viana F. 2008. Hypoosmotic- and pressure-induced membrane stretch
activate TRPC5 channels. J. Physiol. 586:5633–49
Gottlieb P, Folgering J, Maroto R, Raso A, Wood TG, et al. 2008. Revisiting TRPC1 and TRPC6
mechanosensitivity. Pflug. Arch. 455:1097–103
Greene CC, McMillan PM, Barker SE, Kurnool P, Lomax MI, et al. 2001. DFNA25, a novel locus for dominant
nonsyndromic hereditary hearing impairment, maps to 12q21-24. Am. J. Hum. Genet. 68:254–60
Greka A, Mundel P. 2012. Cell biology and pathology of podocytes. Annu. Rev. Physiol. 74:299–323
Grimm C, Cuajungco MP, van Aken AF, Schnee M, Jors S, et al. 2007. A helix-breaking mutation in TRPML3
leads to constitutive activity underlying deafness in the varitint-waddler mouse. Proc. Natl. Acad. Sci. USA
104:19583–88
Grimm C, Kraft R, Sauerbruch S, Schultz G, Harteneck C. 2003. Molecular and functional characterization
of the melastatin-related cation channel TRPM3. J. Biol. Chem. 278:21493–501
Guibert C, Ducret T, Savineau JP. 2011. Expression and physiological roles of TRP channels in smooth
muscle cells. Adv. Exp. Med. Biol. 704:687–706
Hardie RC. 1991. Whole-cell recordings of the light induced current in dissociated Drosophila photoreceptors:
evidence for feedback by calcium permeating the light-sensitive channels. Proc. Biol. Sci. 245:203–10
Hardie RC. 2011. A brief history of TRP: commentary and personal perspective. Pflug. Arch. 461:493–98
Hardie RC, Franze K. 2012. Photomechanical responses in Drosophila photoreceptors. Science 338:260–63
Harrington AM, Hughes PA, Martin CM, Yang J, Castro J, et al. 2011. A novel role for TRPM8 in visceral
afferent function. Pain 152:1459–68
Hartmann J, Dragicevic E, Adelsberger H, Henning HA, Sumser M, et al. 2008. TRPC3 channels are required
for synaptic transmission and motor coordination. Neuron 59:392–98
Hartmannsgruber V, Heyken WT, Kacik M, Kaistha A, Grgic I, et al. 2007. Arterial response to shear stress
critically depends on endothelial TRPV4 expression. PLoS ONE 2:e827
Hayashi T, Kondo T, Ishimatsu M, Yamada S, Nakamura K, et al. 2009. Expression of the TRPM8-
immunoreactivity in dorsal root ganglion neurons innervating the rat urinary bladder. Neurosci. Res.
65:245–51
Hoberg M, Gratz HH, Noll M, Jones DB. 2005. Mechanosensitivity of human osteosarcoma cells and phos-
pholipase C β2 expression. Biochem. Biophys. Res. Commun. 333:142–49
Hsu YJ, Hoenderop JG, Bindels RJ. 2007. TRP channels in kidney disease. Biochim. Biophys. Acta 1772:928–36
Huang J, Liu CH, Hughes SA, Postma M, Schwiening CJ, Hardie RC. 2010. Activation of TRP channels by
protons and phosphoinositide depletion in Drosophila photoreceptors. Curr. Biol. 20(3):189–97

Hunt JL, Pollak MR, Denker BM. 2005. Cultured podocytes establish a size-selective barrier regulated by
specific signaling pathways and demonstrate synchronized barrier assembly in a calcium switch model of
junction formation. J. Am. Soc. Nephrol. 16:1593–602
Hwang RY, Stearns NA, Tracey WD. 2012. The ankyrin repeat domain of the TRPA protein painless is
important for thermal nociception but not mechanical nociception. PLoS ONE 7:e30090
Inoue R, Jensen LJ, Jian Z, Shi J, Hai L, et al. 2009. Synergistic activation of vascular TRPC6 channel
by receptor and mechanical stimulation via phospholipase C/diacylglycerol and phospholipase A2/ω-
hydroxylase/20-HETE pathways. Circ. Res. 104:1399–1409
Inoue R, Jian Z, Kawarabayashi Y. 2009. Mechanosensitive TRP channels in cardiovascular pathophysiology.
Pharmacol. Ther. 123:371–85
Jin M, Berrout J, O’Neil RG. 2011. Regulation of TRP channels by osmomechanical stress. In TRP Channels,
ed. MX Zhu, pp. 189–207. Boca Raton, FL: CRC Press
Jors S, Grimm C, Becker L, Heller S. 2010. Genetic inactivation of Trpml3 does not lead to hearing and
vestibular impairment in mice. PLoS ONE 5:e14317
Kahn-Kirby AH, Dantzker JL, Apicella AJ, Schafer WR, Browse J, et al. 2004. Specific polyunsaturated fatty
acids drive TRPV-dependent sensory signaling in vivo. Cell 119:889–900
Kanai Y, Nakazato E, Fujiuchi A, Hara T, Imai A. 2005. Involvement of an increased spinal TRPV1 sensiti-
zation through its up-regulation in mechanical allodynia of CCI rats. Neuropharmacology 49:977–84
Kang L, Gao J, Schafer WR, Xie Z, Xu XZ. 2010. C. elegans TRP family protein TRP-4 is a pore-forming
subunit of a native mechanotransduction channel. Neuron 67:381–91
Kang S, Jang JH, Price MP, Gautam M, Benson CJ, et al. 2012. Simultaneous disruption of mouse ASIC1a,
ASIC2 and ASIC3 genes enhances cutaneous mechanosensitivity. PLoS ONE 7:e35225
Kashiba H, Uchida Y, Takeda D, Nishigori A, Ueda Y, et al. 2004. TRPV2-immunoreactive intrinsic neurons
in the rat intestine. Neurosci. Lett. 366:193–96
Kawashima Y, Geleoc GS, Kurima K, Labay V, Lelli A, et al. 2011. Mechanotransduction in mouse inner ear
hair cells requires transmembrane channel-like genes. J. Clin. Invest. 121:4796–809
Kerstein PC, del Camino D, Moran MM, Stucky CL. 2009. Pharmacological blockade of TRPA1 inhibits
mechanical firing in nociceptors. Mol. Pain 5:19
Kim C. 2007. TRPV family ion channels and other molecular components required for hearing and proprio-
ception in Drosophila. See Liedtke & Heller 2007, pp. 313–27
Kim J, Chung YD, Park DY, Choi S, Shin DW, et al. 2003. A TRPV family ion channel required for hearing
in Drosophila. Nature 424:81–84
Kim JY, Zeng W, Kiselyov K, Yuan JP, Dehoff MH, et al. 2006. Homer 1 mediates store- and inositol
1,4,5-trisphosphate receptor-dependent translocation and retrieval of TRPC3 to the plasma membrane.
J. Biol. Chem. 281:32540–49
Kim Y, Wong AC, Power JM, Tadros SF, Klugmann M, et al. 2012. Alternative splicing of the TRPC3
ion channel calmodulin/IP3 receptor-binding domain in the hindbrain enhances cation flux. J. Neurosci.
32:11414–23
Kindt KS, Viswanath V, Macpherson L, Quast K, Hu H, et al. 2007. Caenorhabditis elegans TRPA-1 functions
in mechanosensation. Nat. Neurosci. 10:568–77
Kobori T, Smith GD, Sandford R, Edwardson JM. 2009. The transient receptor potential channels TRPP2
and TRPC1 form a heterotetramer with a 2:2 stoichiometry and an alternating subunit arrangement.
J. Biol. Chem. 284:35507–13
Kowase T, Nakazato Y, Yoko O, Morikawa A, Kojima I. 2002. Immunohistochemical localization of growth
factor-regulated channel (GRC) in human tissues. Endocr. J. 49:349–55
Kremeyer B, Lopera F, Cox JJ, Momin A, Rugiero F, et al. 2010. A gain-of-function mutation in TRPA1
causes familial episodic pain syndrome. Neuron 66:671–80
Kroese AB, Das A, Hudspeth AJ. 1989. Blockage of the transduction channels of hair cells in the bullfrog’s
sacculus by aminoglycoside antibiotics. Hear. Res. 37:203–17
Kuipers AJ, Middelbeek J, van Leeuwen FN. 2012. Mechanoregulation of cytoskeletal dynamics by TRP
channels. Eur. J. Cell Biol. 91:834–46

Kwan KY, Allchorne AJ, Vollrath MA, Christensen AP, Zhang DS, et al. 2006. TRPA1 contributes to cold,
mechanical, and chemical nociception but is not essential for hair-cell transduction. Neuron 50:277–89
Lansman JB, Hallam TJ, Rink TJ. 1987. Single stretch-activated ion channels in vascular endothelial cells as
mechanotransducers? Nature 325:811–13
Lauritzen I, Chemin J, Honore E, Jodar M, Guy N, et al. 2005. Cross-talk between the mechano-gated K2P
channel TREK-1 and the actin cytoskeleton. EMBO Rep. 6:642–48
Lev S, Katz B, Minke B. 2012. The activity of the TRP-like channel depends on its expression system. Channels
6:86–93
Li J, Verkman AS. 2001. Impaired hearing in mice lacking aquaporin-4 water channels. J. Biol. Chem.
276:31233–37
Liang X, Madrid J, Saleh HS, Howard J. 2011. NOMPC, a member of the TRP channel family, localizes to
the tubular body and distal cilium of Drosophila campaniform and chordotonal receptor cells. Cytoskeleton
68:1–7
Liao Y, Erxleben C, Yildirim E, Abramowitz J, Armstrong DL, Birnbaumer L. 2007. Orai proteins interact
with TRPC channels and confer responsiveness to store depletion. Proc. Natl. Acad. Sci. USA 104:4682–87
Liedtke W. 2007a. TRPV channels’ role in osmotransduction and mechanotransduction. Handb. Exp. Phar-
macol. 179:473–87
Liedtke W, Choe Y, Marti-Renom MA, Bell AM, Denis CS, et al. 2000. Vanilloid receptor-related osmotically
activated channel (VR-OAC), a candidate vertebrate osmoreceptor. Cell 103:525–35
Liedtke WB. 2007b. TRPV channels’ function in osmo- and mechanotransduction. See Liedtke & Heller
2007, pp. 343–59
Liedtke WB, Heller S, eds. 2007. TRP Ion Channel Function in Sensory Transduction and Cellular Signaling
Cascades. Boca Raton, FL: CRC Press
Liu X, Bandyopadhyay BC, Nakamoto T, Singh B, Liedtke W, et al. 2006. A role for AQP5 in activation
of TRPV4 by hypotonicity: concerted involvement of AQP5 and TRPV4 in regulation of cell volume
recovery. J. Biol. Chem. 281:15485–95
Lockwich T, Singh BB, Liu X, Ambudkar IS. 2001. Stabilization of cortical actin induces internalization of
transient receptor potential 3 (Trp3)-associated caveolar Ca2+ signaling complex and loss of Ca2+ influx
without disruption of Trp3-inositol trisphosphate receptor association. J. Biol. Chem. 276(45):42401–8
Loukin SH, Su Z, Kung C. 2009. Hypotonic shocks activate rat TRPV4 in yeast in the absence of polyunsat-
urated fatty acids. FEBS Lett. 583:754–58
Low SE, Amburgey K, Horstick E, Linsley J, Sprague SM, et al. 2011. TRPM7 is required within zebrafish
sensory neurons for the activation of touch-evoked escape behaviors. J. Neurosci. 31:11633–44
Ma X, Cheng KT, Wong CO, O’Neil RG, Birnbaumer L, et al. 2011a. Heteromeric TRPV4-C1 channels
contribute to store-operated Ca2+ entry in vascular endothelial cells. Cell Calcium 50:502–9
Ma X, Nilius B, Wong JW, Huang Y, Yao X. 2011b. Electrophysiological properties of heteromeric
TRPV4-C1 channels. Biochim. Biophys. Acta 1808:2789–97
Ma X, Qiu S, Luo J, Ma Y, Ngai CY, et al. 2010. Functional role of vanilloid transient receptor potential
4-canonical transient receptor potential 1 complex in flow-induced Ca2+ influx. Arterioscler. Thromb. Vasc.
Biol. 30:851–58
Makino A, Prossnitz ER, Bunemann M, Wang JM, Yao W, Schmid-Schonbein GW. 2006. G protein-
coupled receptors serve as mechanosensors for fluid shear stress in neutrophils. Am. J. Physiol. Cell Physiol.
290:C1633–39
Marcotti W, Geleoc GS, Lennan GW, Kros CJ. 1999. Transient expression of an inwardly rectifying potassium
conductance in developing inner and outer hair cells along the mouse cochlea. Pflug. Arch. 439:113–22
Maroto R, Raso A, Wood TG, Kurosky A, Martinac B, Hamill OP. 2005. TRPC1 forms the stretch-activated
cation channel in vertebrate cells. Nat. Cell Biol. 7:179–85
Matsumoto S, Takeda M, Saiki C, Takahashi T, Ojima K. 1997. Effects of tachykinins on rapidly adapting
pulmonary stretch receptors and total lung resistance in anesthetized, artificially ventilated rabbits.
J. Pharmacol. Exp. Ther. 283:1026–31
Matthews BD, Thodeti CK, Tytell JD, Mammoto A, Overby DR, Ingber DE. 2010. Ultra-rapid activation of
TRPV4 ion channels by mechanical forces applied to cell surface beta1 integrins. Integr. Biol. 2:435–42
Mendoza SA, Fang J, Gutterman DD, Wilcox DA, Bubolz AH, et al. 2010. TRPV4-mediated endothelial
Ca2+ influx and vasodilation in response to shear stress. Am. J. Physiol. Heart. Circ. Physiol. 298:H466–76
Mochizuki T, Sokabe T, Araki I, Fujishita K, Shibasaki K, et al. 2009. The TRPV4 cation channel me-
diates stretch-evoked Ca2+ influx and ATP release in primary urothelial cell cultures. J. Biol. Chem.
284:21257–64
Montag S, Kruger K, Madeja M, Speckmann EJ, Musshoff U. 2004. Contribution of the cytoskeleton and the
phospholipase C signaling pathway to fluid stream-induced membrane currents. Cell Calcium 35:333–43
Montell C, Rubin GM. 1989. Molecular characterization of the Drosophila trp locus: a putative integral mem-
brane protein required for phototransduction. Neuron 2:1313–23
Morita H, Honda A, Inoue R, Ito Y, Abe K, et al. 2007. Membrane stretch-induced activation of a TRPM4-like
nonselective cation channel in cerebral artery myocytes. J. Pharmacol. Sci. 103:417–26
Motter AL, Ahern GP. 2012. TRPA1 is a polyunsaturated fatty acid sensor in mammals. PLoS ONE 7:e38439
Muraki K, Iwata Y, Katanosaka Y, Ito T, Ohya S, et al. 2003. TRPV2 is a component of osmotically sensitive
cation channels in murine aortic myocytes. Circ. Res. 93:829–38
Nagata K, Duggan A, Kumar G, Garcia-Anoveros J. 2005. Nociceptor and hair cell transducer properties of
TRPA1, a channel for pain and hearing. J. Neurosci. 25:4052–61
Nandasena BG, Suzuki A, Aita M, Kawano Y, Nozawa-Inoue K, Maeda T. 2007. Immunolocalization of
aquaporin-1 in the mechanoreceptive Ruffini endings in the periodontal ligament. Brain Res. 1157:32–40
Nauli SM, Alenghat FJ, Luo Y, Williams E, Vassilev P, et al. 2003. Polycystins 1 and 2 mediate mechanosen-
sation in the primary cilium of kidney cells. Nat. Genet. 33:129–37
Nilius B, Honore E. 2012. Sensing pressure with ion channels. Trends Neurosci. 35:477–86
Nilius B, Vriens J, Prenen J, Droogmans G, Voets T. 2004. TRPV4 calcium entry channel: a paradigm for
gating diversity. Am. J. Physiol. Cell Physiol. 286:C195–205
Nishida M, Watanabe K, Sato Y, Nakaya M, Kitajima N, et al. 2010. Phosphorylation of TRPC6 chan-
nels at Thr69 is required for anti-hypertrophic effects of phosphodiesterase 5 inhibition. J. Biol. Chem.
285:13244–53
Nishihara E, Hiyama TY, Noda M. 2011. Osmosensitivity of transient receptor potential vanilloid 1 is syner-
gistically enhanced by distinct activating stimuli such as temperature and protons. PLoS ONE 6:e22246
Numata T, Shimizu T, Okada Y. 2007a. Direct mechano-stress sensitivity of TRPM7 channel. Cell Physiol.
Biochem. 19:1–8
Numata T, Shimizu T, Okada Y. 2007b. TRPM7 is a stretch- and swelling-activated cation channel involved
in volume regulation in human epithelial cells. Am. J. Physiol. Cell Physiol. 292:C460–67
Oancea E, Wolfe JT, Clapham DE. 2006. Functional TRPM7 channels accumulate at the plasma membrane
in response to fluid flow. Circ. Res. 98:245–53
O’Hagan R, Chalfie M, Goodman MB. 2005. The MEC-4 DEG/ENaC channel of Caenorhabditis elegans
touch receptor neurons transduces mechanical signals. Nat. Neurosci. 8:43–50
Okubo K, Matsumura M, Kawaishi Y, Aoki Y, Matsunami M, et al. 2012. Hydrogen sulfide-induced mechan-
ical hyperalgesia and allodynia require activation of both Cav 3.2 and TRPA1 channels in mice. Br. J.
Pharmacol. 166:1738–43
Patel A, Honoré E. 2010. Polycystins and renovascular mechanosensory transduction. Nat. Rev. Nephrol.
6:530–38
Patel A, Sharif-Naeini R, Folgering JR, Bichet D, Duprat F, Honoré E. 2010. Canonical TRP channels and
mechanotransduction: from physiology to disease states. Pflug. Arch. 460:571–81
Pedersen SF, Kapus A, Hoffmann EK. 2011. Osmosensory mechanisms in cellular and systemic volume
regulation. J. Am. Soc. Nephrol. 22:1587–97
Peyronnet R, Sharif-Naeini R, Folgering JH, Arhatte M, Jodar M, et al. 2012. Mechanoprotection by poly-
cystins against apoptosis is mediated through the opening of stretch-activated K2P channels. Cell Rep.
1:241–50
Quick K, Zhao J, Eijkelkamp N, Linley JE, Rugiero F, et al. 2012. TRPC3 and TRPC6 are essential for
normal mechanotransduction in subsets of sensory neurons and cochlear hair cells. Ope. Biol. 2:120068
Ramsey IS, Delling M, Clapham DE. 2006. An introduction to TRP channels. Annu. Rev. Physiol. 68:619–47
Raouf R, Rugiero F, Kiesewetter H, Hatch R, Hummler E, et al. 2012. Sodium channels and mammalian
sensory mechanotransduction. Mol. Pain 8:21

Reiser J, Polu KR, Möller CC, Kenlan P, Altintas MM, et al. 2005. TRPC6 is a glomerular slit diaphragm-
associated channel required for normal renal function. Nat. Genet. 37:739–44
Ricci AJ, Crawford AC, Fettiplace R. 2003. Tonotopic variation in the conductance of the hair cell mechan-
otransducer channel. Neuron 40:983–90
Rohacs T, Thyagarajan B, Lukacs V. 2008. Phospholipase C mediated modulation of TRPV1 channels. Mol.
Neurobiol. 37:153–63
Rugiero F, Drew LJ, Wood JN. 2010. Kinetic properties of mechanically activated currents in spinal sensory
neurons. J. Physiol. 588:301–14
Rugiero F, Wood JN. 2009. The mechanosensitive cell line ND-C does not express functional thermoTRP
channels. Neuropharmacology 56:1138–46
Rusch A, Kros CJ, Richardson GP. 1994. Block by amiloride and its derivatives of mechano-electrical trans-
duction in outer hair cells of mouse cochlear cultures. J. Physiol. 474:75–86
Ruwhof C, van Wamel JT, Noordzij LA, Aydin S, Harper JC, van der Laarse A. 2001. Mechanical stress
stimulates phospholipase C activity and intracellular calcium ion levels in neonatal rat cardiomyocytes.
Cell Calcium 29:73–83
Schnitzler M, Storch U, Meibers S, Nurwakagari P, Breit A, et al. 2008. Gq-coupled receptors as mechanosen-
sors mediating myogenic vasoconstriction. EMBO J. 27:3092–103
Schwander M, Xiong W, Tokita J, Lelli A, Elledge HM, et al. 2009. A mouse model for nonsyndromic deafness
(DFNB12) links hearing loss to defects in tip links of mechanosensory hair cells. Proc. Natl. Acad. Sci.
USA 106:5252–57
Sénatore S, Rami Reddy V, Sémériva M, Perrin L, Lalevée N. 2010. Response to mechanical stress is mediated
by the TRPA channel painless in the Drosophila heart. PLoS Genet. 6:e1001088
Seth M, Zhang ZS, Mao L, Graham V, Burch J, et al. 2009. TRPC1 channels are critical for hypertrophic
signaling in the heart. Circ. Res. 105:1023–30
Sharif-Naeini R, Folgering JH, Bichet D, Duprat F, Delmas P, et al. 2010. Sensing pressure in the cardiovas-
cular system: Gq-coupled mechanoreceptors and TRP channels. J. Mol. Cell Cardiol. 48:83–89
Sharif-Naeini R, Folgering JH, Bichet D, Duprat F, Lauritzen I, et al. 2009. Polycystin-1 and -2 dosage
regulates pressure sensing. Cell 139(3):587–96
Sharif-Naeini R, Witty MF, Séguéla P, Bourque CW. 2006. An N-terminal variant of Trpv1 channel is
required for osmosensory transduction. Nat. Neurosci. 9:93–98
Shen J, Harada N, Kubo N, Liu B, Mizuno A, et al. 2006. Functional expression of transient receptor potential
vanilloid 4 in the mouse cochlea. NeuroReport 17:135–39
Shen WL, Kwon Y, Adegbola AA, Luo J, Chess A, Montell C. 2011. Function of rhodopsin in temperature
discrimination in Drosophila. Science 331:1333–36
Shigetomi E, Tong X, Kwan KY, Corey DP, Khakh BS. 2012. TRPA1 channels regulate astrocyte resting
calcium and inhibitory synapse efficacy through GAT-3. Nat. Neurosci. 15:70–80
Shimizu T, Janssens A, Voets T, Nilius B. 2009. Regulation of the murine TRPP3 channel by voltage, pH,
and changes in cell volume. Pflug. Arch. 457:795–807
Shin YC, Shin SY, So I, Kwon D, Jeon JH. 2011. TRIP Database: a manually curated database of protein-
protein interactions for mammalian TRP channels. Nucleic Acids Res. 39:D356–61
Spassova MA, Hewavitharana T, Xu W, Soboloff J, Gill DL. 2006. A common mechanism underlies stretch
activation and receptor activation of TRPC6 channels. Proc. Natl. Acad. Sci. USA 103:16586–91
Staruschenko A, Jeske NA, Akopian AN. 2010. Contribution of TRPV1-TRPA1 interaction to the single
channel properties of the TRPA1 channel. J. Biol. Chem. 285:15167–77
Steigelman KA, Lelli A, Wu X, Gao J, Lin S, et al. 2011. Polycystin-1 is required for stereocilia structure but
not for mechanotransduction in inner ear hair cells. J. Neurosci. 31:12241–50
Stewart AP, Smith GD, Sandford RN, Edwardson JM. 2010. Atomic force microscopy reveals the alternating
subunit arrangement of the TRPP2-TRPV4 heterotetramer. Biophys. J. 99:790–97
Stiber JA, Zhang ZS, Burch J, Eu JP, Zhang S, et al. 2008. Mice lacking Homer 1 exhibit a skeletal myopathy
characterized by abnormal transient receptor potential channel activity. Mol. Cell. Biol. 28:2637–47
Storch U, Forst AL, Philipp M, Gudermann T, Schnitzler M. 2012a. Transient receptor potential channel 1
(TRPC1) reduces calcium permeability in heteromeric channel complexes. J. Biol. Chem. 287:3530–40
Storch U, Schnitzler M, Gudermann T. 2012b. G protein-mediated stretch reception. Am. J. Physiol. Heart.
Circ. Physiol. 302:H1241–49
Tabuchi K, Suzuki M, Mizuno A, Hara A. 2005. Hearing impairment in TRPV4 knockout mice. Neurosci.
Lett. 382:304–8
Tadros SF, Kim Y, Phan PA, Birnbaumer L, Housley GD. 2010. TRPC3 ion channel subunit immunolocal-
ization in the cochlea. Histochem. Cell Biol. 133:137–47
Thorneloe KS, Sulpizio AC, Lin Z, Figueroa DJ, Clouse AK, et al. 2008. N-((1S)-1-{[4-((2S)-2-
{[(2, 4-dichlorophenyl) sulfonyl] amino}-3-hydroxypropanoyl)-1-piperazinyl]carbonyl}-3-methylbutyl)-
1-benzothiophene-2-carboxamide (GSK1016790A), a novel and potent transient receptor potential
vanilloid 4 channel agonist induces urinary bladder contraction and hyperactivity: part I. J. Pharmacol.
Exp. Ther. 326:432–42
Tian D, Jacobo SM, Billing D, Rozkalne A, Gage SD, et al. 2010. Antagonistic regulation of actin dynamics
and cell motility by TRPC5 and TRPC6 channels. Sci. Signal. 3:ra77
Tong Q, Hirschler-Laszkiewicz I, Zhang W, Conrad K, Neagley DW, et al. 2008. TRPC3 is the
erythropoietin-regulated calcium channel in human erythroid cells. J. Biol. Chem. 283:10385–95
Tracey WD Jr, Wilson RI, Laurent G, Benzer S. 2003. painless, a Drosophila gene essential for nociception.
Cell 113:261–73
van Aken AF, Atiba-Davies M, Marcotti W, Goodyear RJ, Bryant JE, et al. 2008. TRPML3 mutations cause
impaired mechano-electrical transduction and depolarization by an inward-rectifier cation current in
auditory hair cells of varitint-waddler mice. J. Physiol. 586:5403–18
Vilceanu D, Stucky CL. 2010. TRPA1 mediates mechanical currents in the plasma membrane of mouse
sensory neurons. PLoS ONE 5:e12177
Volkers M, Dolatabadi N, Gude N, Most P, Sussman MA, Hassel D. 2012. Orai1 deficiency leads to heart
failure and skeletal myopathy in zebrafish. J. Cell Sci. 125:287–94
Walker RG, Willingham AT, Zuker CS. 2000. A Drosophila mechanosensory transduction channel. Science
287:2229–34
Wang Q, Dai XQ, Li Q, Wang Z, Cantero MR, et al. 2012. Structural interaction and functional regulation
of polycystin-2 by filamin. PLoS ONE 7:e40448
Wei H, Karimaa M, Korjamo T, Koivisto A, Pertovaara A. 2012. Transient receptor potential ankyrin 1 ion
channel contributes to guarding pain and mechanical hypersensitivity in a rat model of postoperative
pain. Anesthesiology 117(1):137–48
Welsh DG, Morielli AD, Nelson MT, Brayden JE. 2002. Transient receptor potential channels regulate
myogenic tone of resistance arteries. Circ. Res. 90:248–50
Wes PD, Chevesich J, Jeromin A, Rosenberg C, Stetten G, Montell C. 1995. TRPC1, a human homolog of
a Drosophila store-operated channel. Proc. Natl. Acad. Sci. USA 92(21):9652–56
Winn MP, Conlon PJ, Lynn KL, Farrington MK, Creazzo T, et al. 2005. A mutation in the TRPC6 cation
channel causes familial focal segmental glomerulosclerosis. Science 308:1801–4
Wong F, Schaefer EL, Roop BC, LaMendola JN, Johnson-Seaton D, Shao D. 1989. Proper function of the
Drosophila trp gene product during pupal development is important for normal visual transduction in the
adult. Neuron 3:81–94
Wood JN, Eijkelkamp N. 2012. Noxious mechanosensation: molecules and circuits. Curr. Opin. Pharmacol.
12:4–8
Wu L, Gao X, Brown RC, Heller S, O’Neil RG. 2007. Dual role of the TRPV4 channel as a sensor of flow
and osmolality in renal epithelial cells. Am. J. Physiol. Renal. Physiol. 293:F1699–713
Wu LJ, Sweet TB, Clapham DE. 2010. International Union of Basic and Clinical Pharmacology. LXXVI.
Current progress in the mammalian TRP ion channel family. Pharmacol. Rev. 62:381–404
Xiao R, Xu XZ. 2011. C. elegans TRP channels. Adv. Exp. Med. Biol. 704:323–39
Xie J, Sun B, Du J, Yang W, Chen HC, et al. 2011. Phosphatidylinositol 4,5-bisphosphate (PIP2 ) controls
magnesium gatekeeper TRPM6 activity. Sci. Rep. 1:146
Yin J, Kuebler WM. 2010. Mechanotransduction by TRP channels: general concepts and specific role in the
vasculature. Cell Biochem. Biophys. 56:1–18
Yuan JP, Kim MS, Zeng W, Shin DM, Huang G, et al. 2009. TRPC channels as STIM1-regulated SOCs.
Channels 3:221–25
Yuan JP, Zeng W, Huang GN, Worley PF, Muallem S. 2007. STIM1 heteromultimerizes TRPC channels
to determine their function as store-operated channels. Nat. Cell Biol. 9:636–45
Zakharian E, Cao C, Rohacs T. 2010. Gating of transient receptor potential melastatin 8 (TRPM8) channels
activated by cold and chemical agonists in planar lipid bilayers. J. Neurosci. 30:12526–34
Zhang L, Jones S, Brody K, Costa M, Brookes SJ. 2004. Thermosensitive transient receptor potential channels
in vagal afferent neurons of the mouse. Am. J. Physiol. Gastrointest. Liver Physiol. 286:G983–91
Zhang XF, Chen J, Faltynek CR, Moreland RB, Neelands TR. 2008. Transient receptor potential A1 mediates
an osmotically activated ion channel. Eur. J. Neurosci. 27:605–11
Zhou XL, Loukin SH, Coria R, Kung C, Saimi Y. 2005. Heterologously expressed fungal transient recep-
tor potential channels retain mechanosensitivity in vitro and osmotic response in vivo. Eur. Biophys. J.
34:413–22
Zhu MX. 2011. TRP Channels. Boca Raton, FL: CRC Press
Zhu X, Chu PB, Peyton M, Birnbaumer L. 1995. Molecular cloning of a widely expressed human homologue
for the Drosophila trp gene. 1995. FEBS Lett. 373(3):193–98
Zimon M, Baets J, Auer-Grumbach M, Berciano J, Garcia A, et al. 2010. Dominant mutations in the cation
channel gene transient receptor potential vanilloid 4 cause an unusual spectrum of neuropathies. Brain
133:1798–809

Transient Receptor Potential Channels and Mechanosensation

Uploaded by

Document Information

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Transient Receptor Potential Channels and Mechanosensation

Uploaded by

Copyright:

Available Formats

NE36CH23-Wood ARI 26 May 2013 10:25

on June 5, 2013. (Changes may

Niels Eijkelkamp,1 Kathryn Quick,2

and John N. Wood2

Annu. Rev. Neurosci. 2013. 36:519–46 Keywords

an important role in calcium signaling. Some

TRP INTERACTIONS WITH

OTHER PROTEINS AND

520 Eijkelkamp · Quick · Wood

TRP channels is that the characterization of Pore region

mice, and humans. In yeast, hyperosmotic stim-

www.annualreviews.org • TRP Channels and Mechanosensation 521

To make a compelling case for a mechan-

behavioral or electrophysiological levels

522 Eijkelkamp · Quick · Wood

mechanosensation interact closely with K2P classes of inactivating mechanosensitive cur-

www.annualreviews.org • TRP Channels and Mechanosensation 523

Small DRG (%)

WT TRPC3/ TRPC3 TRPC6 WT TRPC3/ TRPC3 TRPC6 WT TRPC3/

TRPC6 KO KO TRPC6 KO KO (n=73) TRPC6

524 Eijkelkamp · Quick · Wood

single channel conductance and channel num- pt ation

respectively. Both Nanchung and inactive are

www.annualreviews.org • TRP Channels and Mechanosensation 525

526 Eijkelkamp · Quick · Wood

1.0 –160 –120 –80 –40

www.annualreviews.org • TRP Channels and Mechanosensation 527

process of vascular mechanotransduction. Sub- acetylcholine-induced vasodilation is normal

528 Eijkelkamp · Quick · Wood

Table 1 TRP channels and mechanosensation

Subfamily and Mechanosensitive

Flies TRPV NAN Auditory IAV Chordotonal organs Kim (2007)

respond to changes in intraluminar pressure increase in native TRPM7 current amplitude

530 Eijkelkamp · Quick · Wood

precise mechanisms that underpin osmosen- to be mechanically gated, TRPV1-deﬁcient

www.annualreviews.org • TRP Channels and Mechanosensation 531

532 Eijkelkamp · Quick · Wood

with the mechanosensitive channel TREK-1 or contribute to mechanosensitive channels

(Lauritzen et al. 2005). may explain the cell-type-speciﬁc expression of

HEK 293 cells CHO K1

0 1.8 3.6 5.4 7.2 9.0

–100 Empty vector

www.annualreviews.org • TRP Channels and Mechanosensation 533

et al. 2011). TRPV4 can be activated by shear

534 Eijkelkamp · Quick · Wood

Indirect Activation been overviewed (Rohacs et al. 2008). The role

fective (Carrillo et al. 2012). Sphingosine-1-

that TRP channels are not directly gated

www.annualreviews.org • TRP Channels and Mechanosensation 535

Positive Cell swelling Shear stress

Dual tether Single tether

536 Eijkelkamp · Quick · Wood

www.annualreviews.org • TRP Channels and Mechanosensation 537

538 Eijkelkamp · Quick · Wood

of blood-brain barrier endothelial cells. Brain Res. 1436:1–12

www.annualreviews.org • TRP Channels and Mechanosensation 539

mechanical allodynia. Nat. Commun. doi: 10.1038/ncomms2673

540 Eijkelkamp · Quick · Wood

protons and phosphoinositide depletion in Drosophila photoreceptors. Curr. Biol. 20(3):189–97

www.annualreviews.org • TRP Channels and Mechanosensation 541

channels. Eur. J. Cell Biol. 91:834–46

542 Eijkelkamp · Quick · Wood

www.annualreviews.org • TRP Channels and Mechanosensation 543

sensory mechanotransduction. Mol. Pain 8:21