ANRV313-BI76-17 ARI 8 May 2007 21:51
TRP Channels
Kartik Venkatachalam and Craig Montell
Departments of Biological Chemistry and Neuroscience, The Johns Hopkins
University School of Medicine, Baltimore, Maryland 21205; email: cmontell@jhmi.edu
Annu. Rev. Biochem. 2007. 76:387–417
The Annual Review of Biochemistry is online at
biochem.annualreviews.org
This article’s doi:
10.1146/annurev.biochem.75.103004.142819
Copyright c 2007 by Annual Reviews.
All rights reserved
0066-4154/07/0707-0387$20.00
Key Words
calcium, diacylglycerol, kidney disease, mucolipidosis type IV,
phospholipase C, sensory transduction
Abstract
The TRP (Transient Receptor Potential) superfamily of cation channels
is remarkable in that it displays greater diversity in activation
mechanisms and selectivities than any other group of ion channels.
The domain organizations of some TRP proteins are also unusual,
as they consist of linked channel and enzyme domains. A unifying
theme in this group is that TRP proteins play critical roles in sensory
physiology, which include contributions to vision, taste, olfaction,
hearing, touch, and thermo- and osmosensation. In addition, TRP
channels enable individual cells to sense changes in their local environment.
Many TRP channels are activated by a variety of different
stimuli and function as signal integrators. The TRP superfamily is divided
into seven subfamilies: the five group 1 TRPs (TRPC, TRPV,
TRPM, TRPN, and TRPA) and two group 2 subfamilies (TRPP
and TRPML). TRP channels are important for human health as
mutations in at least four TRP channels underlie disease.
387
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TRP: Transient
Receptor Potential
Contents
INTRODUCTION. . . . . . . . . . . . . . . . . 388
TRP Classification and
Phylogenetic Distribution . . . . . 388
ACTIVATION AND
REGULATION OF CHANNEL
ACTIVITY . . . . . . . . . . . . . . . . . . . . . . 390
Invertebrate TRPCs . . . . . . . . . . . . . 390
Mammalian TRPCs . . . . . . . . . . . . . . 392
TRPV . . . . . . . . . . . . . . . . . . . . . . . . . . . 394
TRPM. . . . . . . . . . . . . . . . . . . . . . . . . . . 396
TRPA and TRPN . . . . . . . . . . . . . . . . 398
TRPP . . . . . . . . . . . . . . . . . . . . . . . . . . . 399
TRPML . . . . . . . . . . . . . . . . . . . . . . . . . 400
HETEROMULTIMERIZATION
AMONG TRP PROTEINS . . . . . . 401
SUPRAMOLECULAR
COMPLEXES . . . . . . . . . . . . . . . . . . . 402
The Drosophila Signalplex . . . . . . . . . 402
Mammalian TRP-Containing
Signaling Complexes . . . . . . . . . . 402
FUNCTIONS OF TRPs . . . . . . . . . . . . 403
Sensing the Outside World . . . . . . . 403
Sensing the Local Cellular
Environment. . . . . . . . . . . . . . . . . . 406
TRP CHANNELS AND DISEASE . 408
Hypomagnesemia and
Hypocalcemia Owing to
Mutations in TRPM6 . . . . . . . . . 408
TRPC6, Podocyte Function, and
Kidney Disease. . . . . . . . . . . . . . . . 408
TRPPs and Autosomal Dominant
Polycystic Kidney Disease . . . . . 408
TRPML1 and Mucolipidosis
Type IV. . . . . . . . . . . . . . . . . . . . . . . 409
Oxidative Stress, Constitutively
Active TRPs, and Neuronal
Cell Death . . . . . . . . . . . . . . . . . . . . 409
FUTURE PERSPECTIVES . . . . . . . . 410
INTRODUCTION
Members of the TRP (Transient Receptor
Potential) superfamily of channels share
the common features of six transmembrane
segments, varying degrees of sequence homology,
and permeability to cations. Despite
these similarities, TRP channels are highly
unusual among the known families of ion
channels in that they display an impressive diversity
of cation selectivities and specific activation
mechanisms. Perhaps most amazing
is that a single TRP channel can be activated
through seemingly disparate mechanisms. In
many cases, TRPs can be considered as multiple
signal integrators, as the response to one
input is modified by another. Nevertheless,
a common thread among the superfamily is
that TRP channels play critical roles in the
responses to all major classes of external stimuli,
including light, sound, chemicals, temperature,
and touch. TRP channels also imbue individual
cells with the ability to sense changes
in the local environment, such as alterations
in osmolarity.
TRP Classification and Phylogenetic
Distribution
TRP channels are expressed and function
in a great variety of multicellular organisms,
including worms, fruit flies, zebrafish,
mice, and humans. The TRP superfamily is
broadly divided into groups 1 and 2, which
are themselves divided into seven subfamilies
(Figure 1) (1). An eighth subfamily, TRPY,
consists of yeast TRPs, which are distantly related
to the group 1 and group 2 TRPs (2, 3).
The existence of TRPs in yeast indicates that
the origin of TRP channels predates the emergence
of metazoan organisms.
The separation of the group 1 and 2 TRPs
is based on sequence and topological differences.
The group 1 TRPs consist of five subfamilies,
which bear the strongest sequence
homology to the founding member of the superfamily,
Drosophila TRP (4). Those channels
most related to Drosophila TRP are referred
to as the classical or TRPC channels.
The TRPV, TRPM, TRPA, and TRPN subfamilies
are so named based on the original
name of the initially described member of
each subfamily. Depending on the organism,
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Figure 1
The TRP superfamily. (a) Single members from each of the five group 1 subfamilies. (b) Single members
from each of the two group 2 subfamilies. The following domains are indicated: A, ankyrin repeats; cc,
coiled-coil domain; protein kinase domain; TRP domain. Also shown are transmembrane segments
(vertical rectangles) and pore loop (P), allowing the passage of cations (+++). (c) Composition of the
TRP superfamily in worms, flies, mice, and humans. 1Human TRPC2 is a pseudogene and is not
counted. 2TRPP1-like proteins are not counted. Modified and reprinted with permission from
Reference 1.
the group 1 TRP family consists of between
11 and 22 members (Figure 1c). The TRPN
proteins are not found in mammals, although
they are expressed in some vertebrates, such
as zebrafish.
The group 1 TRPs include several notable
sequence elements and domains. The largest
region of sequence homology spans the six
transmembrane segments, including the pore
loop situated between the fifth and sixth transmembrane
segments (Figure 1a). TRPC,
TRPM, and TRPN channels also contain a
TRP domain, which follows the sixth transmembrane
segment (Figures 1 and 2). The
most conserved portions of the TRP domain
are the TRP boxes 1 and 2 (Figure 2). With
the exception of the TRPM channels, the
TRPs in group 1 have multiple N-terminal
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WW
W
W
W
W
W
W
W
W
L P P P I
P P P F I
L P P P I
L P P F I
L P P F I
L P P P I
L P P P I
P P F I
L P P P F I
K F Q R Y Q L I M H R P
K F Q R L I E Y H R P
K F Q R Y Q L I M H E R P
K Q R Y L I E H R P
K F Q R Y L I E Y H E R P
K R Y I M Y H E P
K Q R Y I M Y H E P
K F Q R Y L E Y R
F Q R M E Y P
V
V
V
V
E W K F G R A V L I R M K S P S P N
E W K F G R A L I R M K S P S P N
E W K F A R K L W L S Y F
E W K F A R S K L L S Y F E
E W K F A R S K L W L S Y F
E W K F A R K L W S Y F E E
E W K F A R K L W S Y F E
E W K F A R K L W S Y F E E
E W K F A R K L W L S Y F E
E W K F A R S L W S Y F E
E W K F A R K L W S Y F E
E W K F A R S K L W S Y F E E
T L P P P F N
G T L P P F N
G T L P P P F
G G T L P P F N
G G T L P P P F N
G T L P P F N
G T L P P F N
G G T P P P F N
T L P P P F N
G G T P P P F N
A X L I R X M X K S XX Y
X L I M E
Y
H E R P
V
F
A
T K L W
L
S Y F
E E
G
G
T
S
M D D X
X P S P X N
L P P P
F
I
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L P P P F N
E W K F G R
W K F Q R
E W K F A R
M
A
L
A
A
L
L
I F
T F D
H D E G
T F
R R F S
N V
Y N R Y T K
Y H F A K
F V Q C S L
M F T V V Q Q K
A
A
A
W
N
-
-
-
-
-
-
-
-
D
S
K
R G I F
I Q N A T I-
-
A
A D D
Y R
D D
T M
T M D
A F
A D
Q M D
T M D
I
K C
L V
K S
T
R V
R A
I
S A
C
TRPM1
TRPM2
TRPM3
TRPM4
TRPM5
TRPM6
TRPM7
TRPM8
dTRPM
cNOMPC
zTRPN1
TRPC1
TRPC2
TRPC3
TRPC4
TRPC5
TRPC6
TRPC7
TRP
TRPL
TRPγ
TRP domain
TRP box 1 TRP box 2
Figure 2
The TRP domain. Highly conserved region of 23–25 amino acids
C-terminal to the transmembrane domains in TRPCs, TRPNs, and
TRPMs. TRP box 1 is invariant in TRPCs, and variations of TRP box 1
are also present in TRPNs and TRPMs. The TRP box 2 is a proline-rich
region. Sequences are from mammals, except zTRPN1 is from zebrafish;
cNOMPC is from Caenorhabditis elegans; and TRP, TRPL, TRPγ, and
dTRPM are from Drosophila.
PLC: phospholipase
C
ankyrin repeats. Three TRPM proteins are
so-called chanzymes (5), with C-terminal enzyme
domains.
The two subfamilies TRPP and TRPML
comprise the group 2 TRPs, which are distantly
related to the group 1 TRPs. The
TRPP and TRPML proteins share sequence
homology over the transmembrane segments
and contain a large loop separating the first
two transmembrane domains (Figure 1b).
The TRPP subfamily may be the most ancient,
as members of this subfamily extend
from yeast to mammals (6). The founding
TRPP and TRPML proteins were discovered
as gene products mutated in autosomal dominant
polycystic kidney disease (ADPKD) and
mucolipidosis type IV (MLIV), respectively
(7–10). Mutations in two group 1 TRP proteins
also underlie human diseases. Autosomal
dominant segmental glomerulosclerosis
results from disruption of TRPC6 (11, 12),
and mutations in TRPM6 cause hypomagnesemia
and hypocalcemia (13, 14). Thus TRP
channels are also of relevance to human health
and disease.
ACTIVATION AND
REGULATION OF CHANNEL
ACTIVITY
The mechanism(s) through which a given
TRP is activated and regulated cannot be
predicted reliably on the basis of its subfamily
assignment. For example, thermally
activated TRPs belong to members of the
TRPV, TRPM, and TRPA subfamilies, while
regulated exocytosis stimulates cation influx
via several TRPC, TRPV, and TRPM channels.
However, in some cases there are similarities
among subfamily members, as all
TRPC channels are activated through pathways
coupled to stimulation of phospholipase
C (PLC). The recurring theme is that
most TRP channels are activated through a
diversity of mechanisms. Remarkably, there
are TRP channels, such as TRPV1, which respond
to stimuli ranging from heat to botanical
compounds, proinflammatory agents, and
exocytosis.
Invertebrate TRPCs
The gene encoding the first member of the
TRP superfamily, Drosophila TRP (4), is required
for maintaining the light response (15).
The Drosophila phototransduction cascade is
initiated when light strikes the G-proteincoupled
receptor rhodopsin. This leads to
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stimulation of a heterotrimeric G protein, activation
of PLC, and subsequent cation influx
into the photoreceptor cells (15). Mutations
in the trp locus result in a transient
light response, characterized by a tenfold decrease
in Ca2+
entry (16). These results indicate
that Drosophila TRP is either a Ca2+
permeable cation channel or a regulatory protein
required for channel activation. The predicted
TRP topology, consisting of multiple
transmembrane segments (4), combined with
heterologous expression studies (17, 18), indicated
that TRP was a new type of Ca2+
permeable
cation channel.
The presence of a transient light response
in the absence of functional TRP indicates a
role for additional channels. Indeed, there are
two other TRPC channels expressed in flies,
TRPL (TRP-like) and TRPγ (19, 20), and the
light response is eliminated in flies with mutations
in both trp and trpl (21). Although TRP
is the major source for Ca2+
entry in the fly
eye (16, 21), TRPL has a role in maintaining
a sustained response during prolonged illuminations
(22). Whereas TRP channels are relatively
selective for Ca2+
, TRPL and TRPγ
are nonselective cation channels (23).
A key question concerns the mechanisms
through which stimulation of
PLC leads to the activation of TRP and
TRPL in vivo. Stimulation of PLC cleaves
phosphoinositide-4,5-bisphosphate (PIP2),
leading to the production of diacylglycerol
(DAG) and the soluble second messenger
inositol-1,4,5-trisphosphate (IP3). There
are at least three models for the mechanism
by which TRP and TRPL may be activated.
According to one model, IP3 diffuses
rapidly through the cytoplasm and binds to
Ca2+
-permeable IP3 receptors present in the
endoplasmic reticulum (ER) membrane.
This leads to Ca2+
release and depletion of
the ER Ca2+
stores, which in turn activates
TRP and TRPL. In fact, Drosophila TRP
and several mammalian TRPCs are activated
through such a store-operated mechanism in
heterologous expression systems (1). However,
neither TRP nor TRPL is activated
TRPL: TRP-like
PIP2:
phosphoinositide-
4,5-bisphosphate
DAG: diacylglycerol
IP3: inositol-1,4,5-
trisphosphate
PUFA:
polyunsaturated fatty
acid
by either thapsigargin, a specific inhibitor
of the ER Ca2+
ATPase, or IP3-mediated
store depletion in native photoreceptor cells,
providing evidence against a role of ER Ca2+
store depletion on channel activation in vivo
(24, 25). Furthermore, mutation of the lone
Drosophila homolog of the mammalian IP3
receptor has no effect on channel activation
or the photoresponse (26).
A second model suggests that PLC regulates
Drosophila TRPC activity by reducing
the concentration of inhibitory PIP2. PIP2 has
been reported to inhibit the activity of exogenously
expressed TRPL channels in insideout
patches (27). Therefore, PLC activity
could lead to channel activation by alleviating
the inhibitory effects of PIP2. Although
PIP2 may be inhibitory, depletion of PIP2
may not be sufficient for channel activation
in vivo.
It appears that TRP channel activation is
mediated in vivo by DAG or its metabolites,
polyunsaturated fatty acids (PUFAs). PUFAs
activate TRP and TRPL channels in dissected
photoreceptor cells (28), and DAG/PUFAs
activate TRPL channels expressed exogenously
in insect cells (27, 28). Furthermore,
disruption of the eye enriched DAG kinase,
which phosphorylates DAG to phosphatidic
acid (PA), causes constitutive activity of TRP
and TRPL (29). Although PUFA levels were
not measured in the DAG-kinase mutants, diversion
of DAG to PUFAs instead of PA could
elevate PUFA levels, thereby increasing channel
activity (29). Further evidence for a role
of DAG in TRP activation in vivo is that flies
with mutations in the PA phosphatase (PAP),
which converts PA back to DAG, have small
light responses (30), whereas overexpression
of PAP increases channel activity (31).
The activity of TRPL is also downregulated
by its light-dependent shuttling out of
the phototransducing portion of the photoreceptor
cells, the rhabdomeres, into the extrarhabdomeral
cell bodies (32). A Caenorhabditis
elegans TRPC channel, TRP-3, which
functions in fertilization, undergoes a developmentally
regulated translocation (33). In
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cTRPA1
Pain
AMO
cPKD-2
dTRPML
CUP-5
Nan
OSM-9
dTRPA1
cTRP-3
cNOMPC
NOMPC
dTRPM
GON-2
TRP
TRPP2
TRPP3
TRPP5
TRPML2
TRPML3
TRPML1
TRPM4
TRPM5
TRPM2
TRPM8
TRPV1
TRPV2
TRPV3
TRPV4
TRPV5
TRPV6
TRPA1
TRPC6
mTRPC2
zTRPN1
TRPM1
TRPM3
TRPM6
TRPM7
TRPC4
TRPC5
TRPC1
TRPC3
TRPC7
TRPC
TRPN
TRPM
TRPV
TRPP
TRPA
TRPML
Figure 3
Phylogenetic tree showing the relatedness of the TRP proteins. The
dendrogram of vertebrate TRPs includes mostly human TRPs, except for
mouse TRPC2 (cartoon of a mouse) and zebrafish TRPN1 (cartoon of a
zebrafish). White text and cartoons highlight the TRP proteins from
worms and flies. One C. elegans and one Drosophila member of each
subfamily are included.
spermatids, TRP-3 is situated in intracellular
vesicles; however, during sperm activation,
the channel translocates to the plasma membrane.
This translocation is correlated with an
increase in TRP-3 activity.
Mammalian TRPCs
The first mammalian homologs of Drosophila
TRPs identified were referred to as TRPC1,
TRPC2, and TRPC3 (34, 35). Since then,
seven mammalian TRPC proteins (TRPC1–
7) have been described (36) (Figure 3,
Table 1). However, humans express only six
because human TRPC2 is a pseudogene (34).
The seven mammalian homologs share ≥30%
amino acid identity with each other and with
the Drosophila TRPCs over the N-terminal
750–900 amino acids. Based on amino acid
similarities, the mammalian TRPCs fall into
four subsets: TRPC1, TRPC2, TRPC3/6/7,
and TRPC4/5. Whereas some TRPCs (such
as TRPC1) are broadly expressed (34, 35),
others are enriched in the nervous system
(Table 1).
All mammalian TRPCs require PLC for
activation (1, and references therein). However,
there is variability in their selectivities for
Ca2+
versus other cations and in the mechanisms
coupling PLC activity to channel stimulation.
Several TRPC proteins may be activated
by depletion of Ca2+
from internal
stores, brought about by application of either
IP3 or thapsigargin (listed in Reference 37)
(Table 1). However, the dependence of exogenously
expressed TRPC-channel activity
on store depletion is controversial (1 and 37,
and references therein).
One hypothesis regarding the relationship
between the status of the Ca2+
stores
and TRPC channel activity is that there
is direct conformational coupling between
TRPCs and ER Ca2+
release channels. Such a
coupling mechanism would require close apposition
between the ER and plasma membranes.
Indeed, separation of the two membranes
by pharmacological reorganization of
the actin cytoskeleton into a cortical ring prevents
the activation of exogenously expressed
TRPC3 channels (38). However, modifying
the actin cytoskeleton may also decrease
channel activity by leading to their internalization
(39). Although requirements for direct
interactions between TRPCs and ER
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Table 1 Properties of vertebrate TRPC and TRPV proteins
Gene
name
Chromosomal
localization
Selectivity
PCa:PNa
Modulation of activity Highest expression
TRPC subfamily
TRPC1 3q22–q24 Nonselective Store depletion, conformational
coupling, mechanical stretchb
Heart, brain, testis, ovary, liver,
spleen
TRPC2a 7, 50.0 cM 2.7 Diacylglycerol (DAG) VNO, testis
TRPC3 4q27 1.6 Store depletion, conformational
coupling, DAG, exocytosis
Brain
TRPC4 13q13.1–q13.2 7 Store depletion (?), exocytosis Brain, endothelia, adrenal gland,
retina, testis
TRPC5 Xq23 9.5 Store depletion (?),
sphingosine-1-phosphate, exocytosis
Brain
TRPC6 11q21–q22 5 Conformational coupling, DAG, PIP3 Lung, brain, placenta, ovary
TRPC7 5q31.2 1.9c, 5d Store depletion, DAG Eye, heart, lung
TRPV subfamily
TRPV1 17p13.3 3.8 (heat),
9.6
(vanilloids)
Heat (43◦C), vanilloids, anandamide,
camphor, piperine (black pepper),
allicin (garlic), ethanol, nicotine,
proinflammatory cytokines, protons,
PIP2, phosphorylation exocytosis
TG, DRG, neurons, urinary
bladder, testis
TRPV2 17p11.2 3 Heat (52◦C), osmotic cell swelling,
exocytosis
DRG, spinal cord, brain, spleen,
intestine
TRPV3 17p13.3 2.6 Warm (33–39◦C); PUFAs; menthol;
compounds from oregano, cloves, and
thymes
TG, DRG, spinal cord, brain,
keratinocytes, tongue
TRPV4 12q24.1 6 Warm (27–34◦C), osmotic cell
swelling, 5 6 -EET, exocytosis
DRG, kidney, lung, spleen, testis,
heart, keratinocytes, heart, liver,
endothelia
TRPV5 7q35 >100 Low intracellular Ca2+,
hyperpolarization, exocytosis
Kidney, intestine, pancreas,
placenta
TRPV6 7q33–q34 >100 Store depletion, exocytosis Small intestine, pancreas, placenta
a
Chromosomal localizations apply to human genes except TRPC2, which is a pseudogene in humans.
Therefore, the chromosomal localization of mouse TRPC2 is provided.
b
Abbreviations: Question mark depicts controversial results; DRG, dorsal root ganglia; PIP2, phosphoinositide-4,5-bisphosphate; PIP3,
phosphatidylinositol 3,4,5-trisphosphate; PUFAs, polyunsaturated fatty acids; TG, trigeminal ganglia; VNO, vomeronasal organ.
c
Spontaneous current.
d
ATP-enhanced current.
Ca2+
release channels (both IP3 and ryanodine
receptors) have been described (1 and
37, and references therein), TRPC channels
are completely functional in DT40 avian Blymphocytes
in which all three IP3-receptor
homologs are knocked out (40–42). However,
a role for conformational coupling
cannot be excluded because TRPC channel
activation could be coupled to ryanodine
receptors in the absence of functional IP3
receptors.
Several mammalian TRPCs are coupled
to PLC activation owing to a requirement
for DAG. When expressed exogenously, some
TRPC channels are potently stimulated by
DAG and its analogs (43) (Table 1). Supporting
a role for DAG in vivo, native TRPC2
channels, which are expressed in the mouse
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PKC: protein kinase
C
vomeronasal organ (VNO) (44), are activated
exclusively by DAG, and not by IP3 receptors,
Ca2+
stores, or the PUFA arachidonic
acid (45). Furthermore, elimination of native
TRPC6/7 channels in cultured cells prevents
the development of DAG-dependent conductances
(46, 47). At least one TRPC channel,
TRPC1, is mechanically gated as it is activated
by the development of tension across the lipid
bilayer in reconstituted liposomes (48) in the
absence of proteins.
The discrepancies with regard to the
activation mechanisms of TRPC channels
underscore the complications in arriving at
conclusions based exclusively on heterologous
expression studies. A native TRPC3mediated
conductance in primary pontine
neurons from neonatal rat brains is activated
through a pathway initiated by the neurotrophin
brain-derived neutotrophic factor
(BDNF) and the TrkB receptor (49). This
native conductance (IBDNF) depends on PLC
stimulation, an elevation of cytosolic Ca2+
,
and functional IP3 receptors (49). Surprisingly,
IBDNF is not gated by DAG (49), raising
the question as to why TRPC3 is activated
by DAG when overexpressed in tissue culture
cells. DAG is also required for protein
kinase C (PKC)-mediated inactivation
of TRPCs (42), and DAG activates native
TRPC7 in DT40 cells only after PKC inhibition
(50). Therefore, discrepancies in the
observed contributions of DAG to TRPC activation
may reflect distinct contributions of
PKC-mediated inhibition in different cells. In
addition, as described above, there is strong
evidence that some native TRPC conductances
are activated by DAG (45).
Agonist-mediated exocytosis of TRPCs
also modulates the activity of the channels
(1) (Table 1). Incorporation of TRPC4
and TRPC5 into the plasma membrane is
promoted by stimulation of the epidermal
growth factor (EGF) receptor. Activation
of the EGF receptor augments insertion of
TRPC4 through tyrosine phosphorylation of
TRPC4 by Src, which in turn increases interaction
with a scaffold protein, the Na+
/H+
exchanger regulatory factor (NHERF) (51).
EGF-induced translocation of TRPC5 occurs
through a separate mechanism, involving
phosphatidylinositide-3-kinase, the Rho
GTPase Rac1, and phosphatidylinositol 4phosphate
5-kinase (52). In the case of
TRPC3, agonist-induced exocytosis involves
direct interactions with the v-SNARE protein,
vesicle-associated membrane protein 2
(53). Regulated translocation of TRPCs from
internal vesicles raises the possibility that
some TRPCs are constitutively active and
contribute to cation influx by insertion into
the plasma membrane (1).
TRPV
TRPV proteins (Figure 3) share ∼25% homology
with the TRPC channels over a region
spanning transmembrane domains 5 and
6 (1). The C. elegans OSM-9 and rat TRPV1
were the first TRPVs identified (54). The biophysical
features of the OSM-9-dependent
current have not been described, although
PUFAs such as arachidonic acid induce both
Ca2+
transients and characteristic avoidance
behaviors in the ASH neurons, which express
OSM-9 and function in osmosensation,
mechanosensation, and chemosensation (55).
This arachidonic acid-induced Ca2+
rise is not
observed in osm-9 mutants. Mutants with defects
in PUFA biosynthesis show similar behavioral
phenotypes, further suggesting that
OSM-9 may be activated by PUFAs (55).
The first mammalian TRPV was identified
by expression cloning in a search for channels
activated by the inflammatory vanilloid
compound capsaicin, which gives spicy foods
their characteristic hot taste (56) (Figure 3,
Table 1). In addition, TRPV1 is activated by
heat (≥43◦
C) (56) and many other chemicals,
which include an endocannabinoid, anandamide
(57); the topical analgesic, camphor
(58); and the pungent compounds present in
black pepper (piperine) (59) and garlic (allicin)
(60). TRPV1-mediated cation influx initiated
by the application of noxious chemicals
or heat is further enhanced by low pH
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(56). In fact, pH ≤ 5.9, characteristic of proalgesic
tissue acidosis associated with injury, induces
a shift in the thermal activation threshold
of TRPV1 so that it can be activated
at room temperature (1). Shifts in the activation
threshold of TRPV1 and potentiation
of capsaicin-mediated responses are also
brought about by ethanol (61), nicotine (62),
and proinflammatory cytokines (63). Furthermore,
TRPV1 is potentiated by a decrease
in PIP2 levels and PKC-mediated phosphorylation
of the channel, both following PLC
activation induced by proalgesic agents such
as bradykinin and nerve growth factor (1).
Therefore, TRPV1 is a multiple signal integrator
capable of transducing signals evoked
by several noxious stimuli (Table 1).
Activation by heat is also a feature of
TRPV2, TRPV3, and TRPV4. TRPV2 is activated
by noxious heat (≥52◦
C) but not by
capsaicin or changes in pH (64). TRPV1 and
TRPV2 are expressed in distinct dorsal root
ganglia neurons of different sizes (64), maintaining
the fidelity of signaling in response to
different temperatures. TRPV3 and TRPV4
are activated at warm temperatures in the
ranges of 33–39◦
C and 27–34◦
C, respectively
(Table 1) (1).
TRPV2–4 are also polymodally activated
and are capable of integrating various stimuli.
TRPV2 function is upregulated by
phosphatidylinositol-3-kinase activation (65)
and hypotonicity-induced cell swelling (66).
TRPV3 is activated in cultured cells by PLC
stimulation (67); by application of PUFAs
such as arachidonic acid (68); by menthol (69);
and by compounds present in spices such as
oregano, cloves, and thymes (67) (Table 1).
In addition to warm temperatures, TRPV4
is activated by extracellular hypotonicity
(1). The hypotonicity-induced activation of
TRPV4 requires its interaction with the water
channel aquaporin 5 (70). Chemicals
such as anandamide and arachidonic acid
activate TRPV4 via a mechanism involving
cytochrome P450-dependent formation
of epoxyeicosatrienoic acids (71). The different
modes through which TRPV4 can be activated
do not occur through the same mechanism
because a point mutation in the third
transmembrane domain inhibits activation by
heat but not by cell swelling or arachidonic
acid (72) (Table 1).
Consistent with the theme that a change
in osmolarity is an evolutionarily conserved
mode for TRPV activation, the worm TRPVs
(OSM-9 and OCR-2) are required for osmosensation,
although it is unclear if they
are activated directly or indirectly by changes
in osmolarity. Nevertheless, both Drosophila
TRPV proteins, Nanchung and Inactive, are
activated by hypoosmolarity when expressed
in a heterologous expression system (73, 74).
TRPV5 and TRPV6 are distinct from
other TRPV channels in that they are not activated
by heat and are the most Ca2+
selective
(PCa:PNa > 100) of the mammalian TRPs
(1) (Table 1). TRPV6 has been reported to
have properties similar to a store-operated
conductance known as Ca2+
-release-activated
Ca2+
current or CRAC (75). Although the
channels exhibit high Ca2+
selectivity, they
are permeable to monovalent cations in the
absence of extracellular Ca2+
(75). However,
some biophysical properties of TRPV6 and
CRAC have clear distinctions (76), and the
involvement of Ca2+
stores in TRPV6 activation
remains controversial.
Several TRPV channel activities are regulated
by insertion or retention in the plasma
membrane (Table 1). TRPV1 interacts with
members of the SNARE-dependent exocytic
pathway, and these interactions promote
PKC-mediated translocation of TRPV1
to the plasma membrane (77). Furthermore,
proalgesic factors such as nerve growth factor
promote surface insertion of TRPV1 via Src
kinase-mediated tyrosine phosphorylation of
the channel (78). TRPV2 activity may also be
regulated by channel insertion into the plasma
membrane from internal vesicles, induced by
the application of insulin-like growth factor-I
in cultured cells (1). Glycosylation in the pore
loop (79) and interactions with proteins called
PACSINs (involved in synaptic vesicle trafficking)
(80) regulate the surface expression
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of TRPV4. Insertion of TRPV5 and TRPV6
into the plasma membrane regulates their activity
as well (81). Retention of TRPV5 in
the plasma membrane is promoted by the
β-glucuronidase Klotho through hydrolysis
of extracellular sugar residues on the channel
(82).
TRPM
The mammalian TRPM subfamily consists of
eight members (Figure 3), which share ∼20%
amino acid identities to TRPC channels over
the C-terminal five transmembrane domains
(1). Similar to TRPCs, TRPM proteins have
a TRP domain C-terminal to the transmembrane
segments (Figure 2). The total amino
acid lengths (∼1000–2000) and sequences
of the C-terminal regions of these proteins
vary considerably. Based on similarities in
amino acid sequences, these proteins fall into
subsets consisting of TRPM1/3, TRPM4/5,
and TRPM6/7 (Figure 3). TRPM2 and
TRPM8arenotplacedinanysubset,although
they are most closely related to each other.
TRPM2 and TRPM6/7 are unusual in that
they are chanzymes, with C-terminal enzyme
domains.
The first mammalian TRPM identified,
TRPM1, was initially named melastatin, as
its expression levels correlated inversely with
the metastatic potential in some melanomic
cell lines (83). In addition to the full-length
clone (TRPM1-L), a short variant of TRPM1
(TRPM1-S), which is devoid of transmembrane
domains, interacts with TRPM1-L and
inhibits its translocation to the plasma membrane
(84) (Table 2).
TRPM3 forms a constitutively active Ca2+
and Mn2+
permeable channel when expressed
exogenously in cultured cells (85).
The spontaneous TRPM3 currents are enhanced
by hypotonic extracellular solutions
and cell swelling (85) (Table 2). Alternatively,
TRPM3 might be activated by store depletion
(86) or sphingolipids (87). TRPM3 also
has multiple splice variants with distinct ion
selectivities (88).
TRPM4 and TRPM5 are unusual among
the TRP superfamily in that they are
voltage-modulated, Ca2+
-activated, monovalent
cation selective channels (VCAMs)
(89–93) (Table 2). The monovalent selectivity,
which sets these channels apart from other
TRP channels, is dictated by a short acidic
stretch of six amino acids in its pore loop (94).
TRPM4 is expressed as two splice variants (84,
90), one of which (TRPM4b) is a VCAM (89,
93), whereas the other (TRPM4a) displays little
discernible activity (84, 89, 90). The voltage
dependence of TRPM4b and TRPM5
ensures the modulation of both activation
and inactivation by changes in membrane potentials
(91–93). The lack of Ca2+
permeability,
Ca2+
activation, and voltage modulation
suggests that the activities of VCAMs
could be affected by the activity of voltagegated
Ca2+
channels. In turn, VCAM activation
would decrease the membrane potential
and the driving force for Ca2+
through other
channels (90).
TRPM4b and TRPM5, similar to many
other TRP channels, are modulated by PIP2,
with PIP2 reversing the Ca2+
-dependent desensitization
of the channels and thereby
increasing channel activity (91, 95, 96)
(Table 2). TRPM5 is also temperature sensitive
and activated by heat in the range of
15–35◦
C (97) (Table 2). Thus TRPM5 is
another example of a TRP channel that integrates
thermal input with other modes of
activation.
The TRPM6 and TRPM7 channels have
unusual architectures as they are chanzymes
with C-terminal atypical protein kinase domains
(13, 14, 98, 99). TRPM7 is a divalentspecific
cation channel, which is permeable to
virtually all physiological divalent cations including
Mg2+
and trace metals such as Ni2+
(100). It is a Mg2+
-inhibited channel, and
because it fluxes Mg2+
(99), inhibition by
Mg2+
provides an effective mode of feedback
regulation. The TRPM6 chanzyme is also
permeable to trace metals, Mg2+
, and Ca2+
and is inhibited by intracellular Mg2+
(101)
(Table 2).
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Table 2 Properties of vertebrate TRPM, TRPA, and TRPN proteins
Gene
name
Chromosomal
localizationa
Selectivity PCa:PNa Modulation of activity Highest expression
TRPM subfamily
TRPM1 15q13–q14 Nonselective Translocation (?)b Brain, melanosomes
TRPM2 21q22.3 ∼0.3 ADP-ribose, cADP-ribose, pyrimidine
nucleotides, arachidonic acid, NAD,
H2O2, Ca2+
Brain, bone marrow,
spleen
TRPM3 9q21.11 1.6 Osmotic cell swelling, store depletion
(?)
Kidney, brain, pituitary
TRPM4 19q13.33 Monovalent cation
selective
Ca2+, voltage modulated, PIP2 Prostate, colon, heart,
kidney, testis
TRPM5 11p15.5 Monovalent cation
selective
Ca2+, voltage modulated, PIP2, heat
(15–35◦C)
Intestine, liver, lung,
taste cells
TRPM6 9q21.13 Divalent cation selective
(Mg2+ and Ca2+)
Mg2+ inhibited, translocation Kidney, small intestines
TRPM7 15q21 Divalent cation selective
(Mg2+ and Ca2+)
Mg2+ inhibited, ATP, protons,
phosphorylation, PIP2
Kidney, heart, pituitary,
bone, adipose
TRPM8 2q37.2 3.3 Cool (23–28◦C), menthol, icilin, pH
modulated, PIP2
DRG, TG, prostate,
liver
TRPA and TRPN
TRPA1 8q13 0.8 Cold (17◦C) (?), icilin, isothiocyanates
(mustard oil, horseradish, and wasabi),
allicin (garlic), cinnamaldehyde
(cinnamon oil), acrolein (tear gas),
cannabinoids, bradykinin, DAG,
PUFAs, mechanically gated (?)
DRG, hair cells, ovary,
spleen, testis
zTRPN – ? Mechanically gated (?) Ear, eye
a
All chromosomal localizations are of human proteins except for the zebrafish TRPN1 (zTRPN1) because TRPN1 proteins are absent in humans.
b
Abbreviations: Question mark depicts controversial results; DAG, diacylglycerol; DRG, dorsal root ganglia; PIP2,
phosphoinositide-4,5-bisphosphate; PUFAs, polyunsaturated fatty acids; TG, trigeminal ganglia.
TRPM7 activity is regulated by pH, ATP,
lipids, and translocation. TRPM7 is upregulated
tenfold following a decrease in extracellular
pH to 4.0 from the physiological pH
of 7.4 (102). Thus a portion of the TRPM7
pool may be situated in an acidic environment,
such as acidic vesicles. ATP significantly increases
TRPM7 currents (98); however, the
basis for this effect is controversial. TRPM7
activity may be enhanced by ATP, forming
Mg.
ATP, which decreases intracellular free
Mg2+
(99) (Table 2). Alternatively, the requirement
for ATP might reflect consumption
of ATP for PIP2 generation because PIP2
depletion causes a decrease in TRPM7 activity
(103). Relatively rapid plasma membrane
insertion of TRPM7 (<2 min) is induced by
physiologically relevant fluid flow, leading to
an increase in activity (104). TRPM7 is expressed
in a vascular smooth muscle cell line
(104) and could be activated by blood flow in
areas in which the endothelium lining blood
vessels is breached.
The role of the kinase domain of TRPM7
is controversial. According to one study, mutations
in the ATP-binding region of the
kinase domain lead to markedly decreased
channel function (98). Subsequently, it was
reported that mutations in the kinase domain
do not prevent channel activation, although
they change the sensitivity of the channel to
Mg2+
inhibition (105). Nucleotide-mediated
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inhibition of TRPM7 is dependent on the
nucleotide-binding site in the kinase domain,
which works in concert with a Mg2+
-binding
site on TRPM7 outside of the kinase domain
(106). The kinase domain also plays a role in
trafficking or assembly of the channel (107).
TRPM2 is a chanzyme with a Cterminal
ADP-ribose pyrophosphatase domain
(NUDT9 homology domain) (108,
109). TRPM2 forms a Ca2+
permeable
nonspecific cation channel that is activated
by intracellular ADP-ribose, pyrimidine nucleotides,
and NAD (108, 109) (Table 2).
This channel forms a cellular redox sensor and
is activated by peroxide or other agents that
produce reactive oxygen and nitrogen species
(110) (Table 2). This activation of TRPM2
by oxidative and nitrosative stress requires
an intact ADP-ribose binding cleft in the
NUDT9 domain of TRPM2 (111). Furthermore,
cADP-ribose, arachidonic acid, and
intracellular Ca2+
also positively modulate
TRPM2 function (110, 112, 113) (Table 2).
A shorter variant of TRPM2, which is missing
the last four transmembrane domains and
C terminus, acts as a dominant negative inhibitor
of TRPM2 (114).
TRPM8 is a thermally regulated channel
activated by moderately cool temperatures
(<23–28◦
C) and by compounds that evoke
a sensation of coolness, such as menthol,
eucalyptol, and icilin (115, 116) (Table 2).
Activation by cold and menthol can be separated
because several mutations having a profound
effect on activation by menthol have
only minimal effects on activation by cool
temperatures (117). These data indicate that
the domains involved in activation by menthol
and thermal input are distinct. In further
support of this conclusion, modulation
of TRPM8 activity by pH has differential effects
on activation by icilin and cold versus
menthol (118). The mechanism for thermal
activation of TRPV1 and TRPM8 by hot and
cool temperatures, respectively, appears to be
similar (119, 120). These channels are voltage
dependent, and their respective activation
temperatures as well as ligands lead to shifts
in their voltage thresholds toward more physiological
membrane potentials (119, 120).
TRPM8 activity is also regulated by PIP2
(121) (Table 2), as depletion of PIP2 reduces
activity induced by menthol or thermal cool.
PIP2-mediated regulation of TRPM8 is reduced
by mutations in basic residues in the
TRP domain (122). Although these mutations
affect the PIP2-modulated responses to both
menthol and cool (122), they lie close or adjacent
to mutations identified in the screen for
residues that specifically function in the menthol
response (117).
TRPA and TRPN
The first TRPA protein, human TRPA1, was
identified in a screen for genes downregulated
following oncogenic transformation of
fibroblasts (123). TRPA1 is the only TRPA
protein present in humans and other mammals
(1) and was previously called ANKTM1
because the protein consists of many Nterminal
ankyrin repeats. There are two and
four TRPA proteins encoded in the C. elegans
and Drosophila genomes, respectively
(Figure 1c).
TRPA1 is chemically activated by the
psychoactive component in marijuana, environmental
irritants, and pungent compounds.
These include ingredients present
in wasabi, horseradish, and mustard oils
(isothiocyanates); garlic (allicin); cinnamon
oil (cinnamaldehyde); marijuana (tetrahydrocannabinol);
and tear gas (acrolein) (60, 124–
126). TRPA1 can also be activated by stimulation
of the PLC pathway by bradykinin and by
the subsequently produced metabolites DAG
and PUFAs (125) (Table 2).
There is controversy as to whether TRPA1
is a thermally or mechanically gated channel.
When exogenously expressed in cultured
cells, TRPA1 has been reported as
a noxious cold (<17◦
C) activated channel
(125, 127) (Table 2). However, the cold activation
of TRPA1 in both cultured cells (124)
and TRPA1-deficient mice is controversial
(126, 128). TRPA1 channels from mouse and
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zebrafish have been suggested to be mechanically
gated channels, and the multiple ankyrin
repeats of TRPA1 may form a gating spring
capable of transducing mechanical force and
thereby facilitating channel opening (129,
130). However, analyses of TRPA1-deficient
mice described below mitigate this possibility
(126, 128).
Despite the controversy concerning
TRPA1, three Drosophila TRPAs (dTRPA1,
Pyrexia, and Painless) function in thermosensation.
Although TRPA1 may be a cold
thermosensor, Drosophila TRPA1 and Pyrexia
are activated in vitro by warm (≥24–27◦
C)
and noxious (≥40◦
C) heat, respectively
(131–133). Painless has not been functionally
expressed in vitro but is predicted to be
gated by noxious heat (≥38◦
C) and the
isothiocyanates present in wasabi (134, 135).
The TRPN subfamily is so named based
onthefoundingmember,DrosophilaNOMPC
(136). Single TRPN members are present in
worms, flies, and zebrafish, whereas mammals
do not encode any TRPN homologs. These
proteins have 29 ankyrin repeats situated in
tandem N-terminal to the transmembrane
domains. Based on the functional analyses described
below, they are likely to be mechanically
gated, possibly involving a gating spring
comprised of the ankyrin repeats. Presently,
there is a lack of functional information concerning
TRPN’s ability to form channels.
TRPP
TRPP2 (polycystin-2 or PKD2) is the
archetypal TRPP channel and was discovered
as a protein disrupted in ADPKD (10).
TRPP2 and other group 2 TRPs have very
low sequence similarity with members of the
group 1 branch of the TRP superfamily.
The group 2 TRPs are also distinguished
from the group 1 TRPs by a large loop between
transmembrane domains one and two
(Figure 1b). Nevertheless, TRPP2 and the
related mammalian proteins, referred to as
TRPP3 (polycystin-L, PKD2L1) and TRPP5
(PKD2L2), have six transmembrane segments
(1). Invertebrate TRPPs have been described
in C. elegans (137), Drosophila (AMO) (138,
139), and the sea urchin (suPC2) (140).
TRPPs might comprise the most primitive
TRP subfamily, as microbial homologs of
TRPP2 are found in yeast (6).
The transmembrane segments in TRPP2
have sequence homology with 6 of the 11
C-terminal transmembrane domains of another
protein disrupted in ADPKD, referred
to as TRPP1 (polycystin-1 or PKD1) (141).
This protein, which includes a ∼2500-amino
acid extracellular domain, is also referred to as
TRPP1, based on its sequence relatedness to
TRPP2. TRPP2 binds to TRPP1, and this association
induces the translocation of TRPP2
to the plasma membrane where it serves as
a Ca2+
permeable nonselective cation channel
(1) (Table 3). Translocation of TRPP2 to
the primary cilia, where it is localized in many
cells, requires a stretch of 15 amino acids on
the N terminus of TRPP2 and is independent
of TRPP1 (142). Chaperone-like factors
can also induce translocation of TRPP2
to the plasma membrane from intracellular
pools (143, 144). The TRPP1/TRPP2 complex
may contribute to TRPP2 function at the
plasma membrane because anti-TRPP1 antibodies
can induce structural rearrangements
leading to TRPP2 activation (145). Furthermore,
the addition of a C-terminal fragment
of TRPP1 enhances the channel activity of
TRPP2 (146).
Activation of TRPP2 may occur through
mechanical gating or via a transduction pathway
initiated by growth factors. The presence
of TRPP proteins on both motile and primary
cilia could render them capable of sensing
fluid flow, osmolarity, and mechanical stretch.
Accordingly, TRPP1 and TRPP2 have been
implicated in flow-induced Ca2+
elevation in
cultured kidney cells (147) (Table 3). Furthermore,
TRPP2-deficient embryos do not
display the normal flow-induced intracellular
Ca2+
elevation at nodal cilia (148). TRPP2 increases
EGF-induced, PLC-dependent Ca2+
influx in cultured kidney epithelial cells (149).
EGF activates TRPP2-dependent Ca2+
influx
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Table 3 Properties of vertebrate TRPP and TRPML proteins
Gene
name
Chromosomal
localizationa
Selectivity
PCa:PNa
Modulation of activity Highest expression
TRPP2 4q21–q23 Nonspecific Ca2+, translocation, TRPP1, EGF,
PIP2, fluid flow, actin cytoskeletonb
Widely expressed, kidney
TRPP3 10q24 4.3 Ca2+ Kidney, heart
TRPP5 5q31 – – Testis, heart
TRPML1 19p13.2–p13.3 Monovalent cation
selective (?)
pH, Ca2+, proteolytic cleavage Brain, heart, skeletal muscle
TRPML2 1p22 – – –
TRPML3 1p22.3 – – Cochlear hair cellsc
a
All chromosomal localizations are of human proteins.
b
Abbreviations: Question mark depicts controversial results; EGF, epidermal growth factor; PIP2, phosphoinositide-4,5-bisphosphate.
c
Localization performed in the mouse.
by lifting PIP2-induced inhibition of TRPP2
(149). Reconstitution of TRPP2 in lipid bilayers
and exogenous expression in cultured
cells lead to the development of a Ca2+
permeable,
nonselective cation channel with multiple
conductance states that are inhibited
by Ca2+
and the diuretic amiloride (150)
(Table 3). The channel activity of TRPP2 in
lipid bilayers is enhanced by its interaction
with α-actinin, implicating a role for the actin
cytoskeleton in the modulation of TRPP2
(151).
In addition to functioning as a cation influx
channel, TRPP2 is also localized in the ER
membrane where it is proposed to serve as a
new type of Ca2+
release channel (152). The
C. elegans homolog of TRPP2 also appears
to be a Ca2+
release channel and modulates
IP3- and ryanodine-mediated Ca2+
release
from intracellular stores (153). Localization
of mammalian TRPP2 to the ER is mediated
by the phosphofurin acidic cluster sorting
protein-2 (PACS-2) interacting with an
acidic cluster in the C terminus of TRPP2
(154). Another study reports that TRPP2 impacts
Ca2+
release by interacting with the IP3
receptor, thereby modulating IP3-mediated
Ca2+
release (155). TRPP3 has been reported
to be a voltage-modulated, Ca2+
-activated
nonselective cation channel (156). TRPP3 is
also permeable to monovalent organic cations
(157).
TRPML
TRPML1 (mucolipin-1 or MCOLN1) is
the founding member of the TRPML subfamily
(7–9). Mutations in this protein
are responsible for the lysosomal storage
disorder mucolipidosis IV, which is characterized
by severe neurodegeneration. In addition
to TRPML1, mammals encode two
other closely related proteins referred to
as TRPML2 and TRPML3 (Figure 3) (1).
TRPML1 and TRPML2 have lysosomal targeting
signals and reside in the lysosomal
membrane (158–160). TRPML3 does not
have such a targeting signal and resides predominantly
in the ER membrane when expressed
in cultured cells (158). The C. elegans
and Drosophila genomes each encode one
TRPML protein (Figure 1c).
TRPML1 is the only member of this subfamily
shown to be a cation channel. When expressed
in Xenopus oocytes, TRPML1 translocates
to the plasma membrane upon elevations
in intracellular Ca2+
and is reported to form
a nonselective Ca2+
channel (161) (Table 3).
Another study found that TRPML1 has multiple
conductance states whose function is
inhibited by a decrease in pH (162). However,
the Ca2+
permeability and pH regulation
of TRPML1 are controversial. TRPML1
has been reported to be a monovalent cation
permeable channel (160) that fluxes protons,
thereby providing a proton leak pathway,
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regulating intralysosomal pH (163). Indeed,
the absence of TRPML1 leads to the acidification
of the lysosomal lumen (163). Cleavage
of TRPML1 by the lysosomal protease
cathepsin B has been reported to inactivate the
channel (160) (Table 3). Since cathepsin B is
highly pH sensitive, this provides an elegant
model for pH-mediated feedback regulation
of TRPML function.
HETEROMULTIMERIZATION
AMONG TRP PROTEINS
A feature shared by many members of the
TRP superfamily of proteins is that closely
related TRP channels form heteromultimers.
Heteromultimerization is an effective mode
for modulating the function, subcellular localization,
and biophysical properties of the
interacting channels. In the Drosophila eye,
TRP is tenfold more abundant than TRPL
or TRPγ and is present primarily as a homomultimer.
However, TRPL appears to
form obligatory heteromultimers, resulting in
TRP/TRPL as well as TRPL/TRPγ heteromultimers
in vivo and when expressed exogenously
in cultured cells (18, 20). Such heteromultimerization
provides a mechanism for
regulating the channel conductance as the
biophysical properties of the heteromultimers
are distinct from those of the homomultimers
(18, 20).
Mammalian TRPC proteins also form heteromultimers.
Heteromultimeric interactions
tend to be favored between members that are
closely related to each other (164, 165), although
this is not a strict rule. TRPC1 is
most related to TRPC4/TRPC5, and TRPC1
and TRPC5 have overlapping distribution
in the hippocampus and form heteromultimeric
channels when coexpressed in cultured
cells (166). Interactions between TRPC1 and
TRPC5 lead to the generation of novel conductances
with biophysical properties distinct
from those of TRPC1 and TRPC5 homomultimers
(166). Furthermore, biochemical
analyses have identified TRPC1, TRPC4, and
TRPC5 heteromultimers in rat embryonic
brains, which form channels with novel conductances
when expressed in vitro (167).
TRPC1 can coassemble with members of
the TRPC3/6/7 subfamily as well (18, 167,
168). Native TRPC3 and TRPC6 interact
with TRPC1 in the rat embryonic brain (167).
Furthermore, a TRPC3-associated conductance
in cultured cells requires coexpression
of TRPC1 (167, 168). Evidence exists for multiple
combinations of interactions between
TRPC1, TRPC3/6, and TRPC4/5 (167).
Such combinations between different TRP
proteins could generate an incredible diversity
of channels with an array of distinct biophysical
properties and biological functions.
Members of other TRP subfamilies also
form heteromultimers. The C. elegans TRPV
proteins OSM-9 and OCR-2 may interact
in vivo, as each is required for the localization
of the other in the sensory cilia
(169). Similar interactions might also exist
between the Drosophila TRPV proteins,
Nanchung and Inactive, as elimination of one
of the two proteins in vivo results in instability
of the other protein (73). TRPV5 and
TRPV6 form heteromultimers (81). TRPM6
and TRPM7 also coassemble, and this interaction
is required for the generation of
a novel conductance larger than that of either
homomultimer and also for the insertion
of TRPM6 into the plasma membrane
(170). Heteromultimerization-induced trafficking
of TRPM6 to the plasma membrane
is of particular significance because mutations
that disrupt the interactions between TRPM6
and TRPM7 prevent TRPM6 from reaching
the plasma membrane, leading to hypomagnesemia
and hypocalcemia (170).
Heteromultimeric interactions among
group 2 TRPs can also effect subcellular
distributions of the channels. The C terminus
of TRPP1 interacts with the C terminus of
TRPP2, and as mentioned above, this interaction
drives the translocation of TRPP2
from intracellular compartments to the
plasma membrane (1). The other group 2
TRP channel, TRPML1, interacts strongly
with the closely related protein TRPML3
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INAD: inactivation
no after potential D
and induces the translocation of the latter
to the lysosomes, which appears to be the
ultimate destination for the TRPML proteins
(158).
SUPRAMOLECULAR
COMPLEXES
Several TRP proteins associate with scaffold
proteins, which link the channels to large
macromolecular assemblies. A key function of
such complexes is to control the subcellular
distribution of the associated TRP channels.
The Drosophila Signalplex
The first evidence for a TRP-containing
signaling complex (signalplex) was demonstrated
in Drosophila photoreceptor cells (23).
The molecular scaffold, which nucleates the
complex, is Inactivation No After Potential
D (INAD), a protein consisting largely of
five PDZ protein-protein interaction modules.
Homomeric interactions between individual
INAD molecules further increase
INAD’s capacity to simultaneously bind multiple
target proteins in the signalplex (23).
The signalplex includes two types of proteins:
core and noncore. The core complex
consists of four proteins—INAD, TRP, PLC
(NORPA), and PKC—which are present at
similar concentrations and are most likely
constitutively bound to INAD (23). Additional
noncore INAD binding proteins are
TRPL, rhodopsin, calmodulin, myosin III
(NINAC), and the immunophilin FKBP59
(23). These noncore proteins are not present
in stoichiometric concentrations with INAD
and may interact transiently with INAD.
A primary function of the signalplex is
to retain the proteins that comprise the
core complex in the light-sensitive microvillar
structures of the photoreceptor cells, the
rhabdomeres (15). Components of the phototransduction
cascade are enriched in the rhabdomeres,
and mutations in the gene encoding
INAD disrupt the rhabdomere localization
of TRP, PLC, and PKC (23). The interaction
with INAD is required for the retention
rather than the targeting of these proteins
to the signalplex (171, 172). Furthermore,
TRP, PLC, and PKC are unstable when
they are not retained in the signalplex owing
to a lack of interactions with INAD (23). This
has important physiological consequences because
altered stoichiometries of these signaling
molecules reduce the overall amplitude
and affect the termination kinetics of the
photoresponse.
There is a reciprocal requirement between
INAD and TRP for retention in the rhabdomeres.
In addition to the dependence on
INAD for the localization of TRP, the retention
of INAD in the rhabdomeres requires
binding to TRP. Thus TRP has an additional
role as an anchoring protein (171, 172).
It might appear intuitive that the primary
function of nucleating the key components
of the phototransduction cascade in the signalplex
is to facilitate fast signaling. This is
a particularly attractive hypothesis because
cation influx takes place within milliseconds
of initiation of the phototransduction cascade.
However, a direct association between
TRP and INAD is not required for rapid
activation because elimination of the TRPINAD
interaction by mutating the INADbinding
site in TRP does not affect the photoresponse
(171). The mutated TRP could
still interact with the signalplex indirectly
via interactions with other INAD binding
proteins. Nevertheless, the signalplex does
play a signaling role because disruption of
the myosin III (NINAC)/INAD interaction
causes a profound delay in response termination.
This defect results from signaling because
noncore INAD binding proteins, such
as the myosin III (NINAC), do not depend on
INAD for normal stability or localization in
the rhabdomeres (23).
Mammalian TRP-Containing
Signaling Complexes
Mammalian TRP channels also appear to be
assembled into macromolecular complexes.
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Native TRPC3 in rat pontine neurons associates
in vivo with the BDNF receptor TrkB
(49). Other members of the TRPC3/TrkB
complex have not been defined. TRPC1 localizes
to cholesterol-enriched lipid raft domains,
caveolae, where it appears to associate
with the IP3 receptor and Gαq (173). Disruption
of caveolae by cholesterol depletion
prevents Ca2+
influx (173). Although this is
only indirect evidence for the involvement of
a macromolecular complex with TRPC1 for
Ca2+
entry, it suggests that disruption of specific
membrane domains such as lipid rafts,
which may harbor TRP-containing macromolecular
complexes, prevents Ca2+
entry.
Mammalian TRPC4 may associate with
a macromolecular complex that includes
the double-PDZ-domain-containing protein
NHERF (or EBP50) (1). Interaction between
TRPC4 and NHERF is required for the
translocation of the channel to the plasma
membrane (1). Furthermore, NHERF can
multimerize, allowing it to cluster additional
proteins. Known NHERF binding proteins
include PLC and the G protein–coupled β2adrenergic
receptor (1).
In addition to PDZ-domain-containing
proteins, components involved in TRP signaling
also interact with different isoforms of
another scaffold protein referred to as Homer.
TRPC1 binds to Homer in the brain and
localizes it to a complex that contains IP3
receptors and group 1 metabotropic glutamate
receptors (mGluR1) (174). The significance
of such a complex tethered by Homer
is underscored by the involvement of native
TRPC1 channels in the development of
mGluR1-induced conductances in Purkinje
neurons (175). Furthermore, Homer 1b exists
in a complex with TRPC3 and IP3 receptors
and mediates both TRPC3 trafficking
and gating by IP3 receptors (176).
FUNCTIONS OF TRPs
The TRP superfamily of channels participates
in a diversity of functions in both excitable
and nonexcitable cells. However, a recurring
theme is that TRP channels have critical roles
in sensory physiology. These include sensory
roles in the broadest sense. TRP channels are
not only essential in allowing animals to sense
the outside world, but also allow individual
cells to sense their local environment.
Sensing the Outside World
TRP channels play critical roles in sensory
modalities, such as touch, hearing, taste, olfaction,
vision, and thermal sensation, in animals
ranging from worms to flies, mice, and
humans.
Chemosensation. Genetic analyses of the C.
elegans osm-9 gene, which encodes one of the
two archetypal TRPV proteins, provided the
first evidence that TRP channels participate in
chemosensation (54). Mutations in osm-9 (as
well as in another TRPV gene, ocr-2) cause
defects in the response to odorants (54, 169).
Given that both osm-9 and ocr-2 are expressed
in neurons that sense odorants, it is likely they
are involved in olfactory transduction. In addition,
the OSM-9 and OCR-2 proteins are
required for multiple sensory modalities, including
nociception and osmosensation (see
below).
Several mammalian TRP channels are required
for chemosensation, one of which
(TRPM5) is a taste transduction channel (177,
178). TRPM5 is broadly required for the taste
modality as the responses to sweet, bitter,
and amino acids are greatly reduced, if not
eliminated, owing to knockout of the mouse
TRPM5 gene (97, 178).
TRPC2 functions in the pheromone response,
which in mammals is mediated
through the VNO. TRPC2 is expressed in
the VNO (44), and TRPC2-deficient male
mice display intriguing behavioral phenotypes
(179, 180). These include a failure to
show aggression toward intruding males and
a propensity to mate with either males or
females. It is noteworthy that TRPC2 is a
pseudogene in humans (34), and the VNO is
generally thought to be a vestigial organ. In
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addition to TRPM5 and TRPC2, thermoTRPs
contribute to the perception of
chemical stimuli and, therefore, function in
chemosensation (see below).
Thermosensation and nociception. Multiple
mammalian TRP channels are activated
by temperature changes and account for a
large proportion of the temperature range
to which mammals respond. As described
above, TRPV1 and TRPV2 are sensors for
uncomfortably warm (>43◦
C) (56) and very
hot (>52◦
C) (64) temperatures, respectively,
whereas TRPV3 (>30–39◦
C) (181–183) and
TRPV4 (∼25–34◦
C) (184, 185) contribute
to the perception of moderate temperatures.
TRPM8 appears to function in our perception
of cool temperatures (115, 116), and
TRPA1 may be a cold sensor (127, 128);
however, this latter conclusion is controversial
(124, 126). Although the thermoTRPs
are expressed in neurons such as those in
the dorsal root or trigeminal ganglia, which
are known to function in thermosensation,
TRPV3 and TRPV4 are also expressed in
skin keratinocytes (181, 184). These channels
appear to be heat activated in these skin
cells (181, 186, 187), although the mechanism
through which temperature stimulation
of keratinocytes contributes to thermosensation
remains a matter of speculation (reviewed
in 188). One possibility is that the activated
keratinocytes release a factor, such as ATP,
which activates an ATP-gated channel in the
sensory neurons that innervate the skin (188).
The requirements for TRPV1, TRPV3,
and TRPV4 in thermosensation have been
confirmed in knockout mice. TRPV1deficient
mice do not display a response to
noxious heat until the temperature is increased
to ∼55◦
C (189, 190). Mice missing
TRPV3 exhibit a thermal preference defect in
a temperature range consistent with the biophysical
analyses. When given a choice between
35◦
C and room temperature, wild-type
animals have a strong bias to occupy the 35◦
C
zone, whereas the TRPV3-knockout mice display
only a slight preference for the higher
temperature (191). TRPV4−/−
mutant mice
also show a variety of behavioral phenotypes,
including an inability to discriminate between
30 and 34◦
C (192, 193).
There are two reports describing TRPA1deficient
mice, and whether these mice are defective
in the cold-temperature detection remains
controversial. According to one study,
TRPA1−/−
mice do not show impairment in
temperature sensitivity (126), whereas a second
study reports a defect in paw withdrawal
from a cold (0◦
C) surface (128). It is unclear
whether these differences result from slightly
different behavioral paradigms, genetic backgrounds,
or the production of truncated versions
of TRPA1, which in turn could affect
other channels.
Despite the controversy concerning the
thermosensory role of TRPA1, all three
Drosophila TRPs known to function in
thermosensation are TRPA proteins. The
Drosophila homolog of the mammalian
TRPA1, dTRPA1, has a role in thermotaxis.
When given a choice between two temperature
zones, 27–31◦
C and 35–41◦
C, wild-type
larvae choose the cooler zone. Reduction of
dTRPA1 expression, using small interfering
RNAs (siRNAs), eliminates this preference
(133). Whereas mammalian TRPA1 may be a
cold sensor (127), dTRPA1 is necessary for detecting
warm temperatures (132, 133). Painless,
the first invertebrate thermoTRP identified,
is required for the avoidance response in
larvae to noxious heat (>39–41◦
C) (134). Another
TRPA protein, Pyrexia, is necessary for
flies to withstand several minutes of exposure
to warm temperatures, such as 40◦
C, without
becoming paralyzed (131).
ThermoTRPs are also required for the response
to chemical stimuli. A shared feature
of mammalian thermoTRPs is that they
respond to chemical stimuli. This property
was initially found for TRPV1, providing a
molecular explanation for the long-known
observation that certain compounds, such as
capsaicin, elicit the same sensation as thermal
heat (56). In addition to displaying impaired
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responses to heat and vanilloid compounds,
TRPV1−/−
mice are deficient in their reaction
to protons and display minimal thermal hyperalgesia
(189, 190), which is enhanced by
proalgesic agents produced at the site of injury.
Thus TRPV1 is a molecular integrator
for noxious thermal and chemical stimuli. Although
a role for TRPA1 as a cold sensor is
still a matter of debate, there is agreement that
TRPA1−/−
animals are deficient in their response
to chemical irritants, such as mustard
oils (126, 128). The Drosophila TRPA Painless
is also required for the avoidance of isothiocyanate,
which is the pungent compound in
wasabi and mustard oils (135).
Thermal and chemical stimuli both affect
TRPM5 activity (97, 177, 178), and this convergence
has fascinating effects on the response
to sweet tastants. Stimulation of the
chorda tympani nerve with sugars is normally
increased by temperatures over the range of
15–35◦
C. However, the residual sugar response
in TRPM5−/−
mice is not augmented
by temperature (97). Thus TRPM5 appears
to be required for the enhanced perception of
sweetness at higher temperatures.
Mechanosensation. At least one thermoTRP
functions in mechanosensation.
TRPV4 is activated in vitro by hypotonicity
(194), and TRPV4−/−
mice display defects
in osmotic regulation (195). The role of
TRPVs in osmosensation is conserved, as
the C. elegans TRPVs OSM-9 and OCR-2
are required for the avoidance of high
osmolarity and mechanical stimuli, in addition
to functioning in chemosensation.
Rat TRPV4 restores normal avoidance to
hypoosmotic and mechanical stimuli in osm-9
mutant worms, when it is expressed in those
neurons (ASH) that normally express osm-9
and function in these modalities (196). A
conundrum is that TRPV4 is activated in
vitro by hypo- rather than hypertonicity. A
role for TRPs in osmosensation also occurs
in yeast, as TRPY proteins function in the
release of Ca2+
from vacuoles in response to
hyperosmotic conditions (2, 3).
The identity of an auditory transduction
channel in mammals is not resolved. Such a
channel is predicted to be expressed at the tip
of the stereocilia in hair cells of the inner ear,
where mechanical force mediated through the
gating spring is thought to open the channels.
TRPA1 was a candidate auditory transduction
channel as it is situated at the tips of the stereocilia,
and the reduction of TRPA1 expression
in zebrafish and in the mouse using morpholinos
and siRNAs, respectively, reduced soundevoked
potentials (129). However, the auditory
response is normal in TRPA1−/−
mice
(126, 128). It has been suggested that TRPA1
may be a hair-cell transduction channel only
during early development because the morpholino
and siRNA analyses were performed
in early stage zebrafish and embryonic mice,
whereas the response in the knockout animals
was analyzed in postnatal mice (128).
Two mammalian TRP channels function
in the auditory response; however, based on
the expression pattern of the channels and/or
the phenotypes of the mutant animals, neither
appears to be a transduction channel. Mice
with severe mutations in TRPML3 exhibit a
variety of phenotypes, including progressive
disorganization of the inner and outer hair
cell bundles (197). TRPML3 is expressed in
vesicles throughout the hair-cell bodies, leading
to the speculation that it functions in
vesicular or intracellular ion homeostasis in
hair cells (197). The auditory response is normal
in young TRPV4−/−
mice; however, in
older mutant mice, there is severe auditory
impairment (198). TRPN1 is suggested to
be a mechanotransduction channel in the zebrafish
because TRPN1 RNA is expressed in
hair cells, and the reduction in TRPN1 expression
in larvae using morpholinos reduces
sound-evoked potentials (199). In the frog the
TRPN1 protein does not appear to be the
transduction channel because it is not situated
in the stereocilia but instead in a motile cilium
in the hair cells (200).
The founding TRPN protein, Drosophila
NOMPC (136), and two Drosophila TRPV
proteins (Nanchung and Inactive) are
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required for auditory sensitivity (73, 74,
201). In wild-type animals, amplification of
auditory signals is nonlinear. Small signals are
more greatly amplified through mechanical
feedback vibrations in the mechanosensory
cells in the antenna. However, nompC mutant
flies show linear amplification at all levels of
sound stimuli (201). The converse is observed
in the nanchung and inactive mutants, both
of which exhibit profound defects in hearing
(73, 74) as a result of excessive amplification
at the lower sound intensities (201). Since the
mechanotransduction channel is expected to
be required for feedback and amplification,
it has been proposed that NOMPC is an
auditory transduction channel (201). There
must be at least one additional such channel,
given that the nompC mutation does not
abolish the auditory response.
The proposal that Drosophila NOMPC
protein is an auditory transduction channel
is consistent with the initial report that it is
a mechanotransduction channel required for
touch (136). The nompC gene is expressed in
mechanosensory organs, and the mechanoreceptor
currents generated in wild-type animals
in response to deflection of the sensory
bristles are absent in nompC flies. The mutant
animals show behavioral phenotypes—
they are uncoordinated and insensitive to a
light touch. The Drosophila trpA gene painless
is dispensable for the normal response
to a light touch but functions in the avoidance
response to noxious mechanical stimuli
(134). The worm NOMPC homolog TRP-4
is a stretch-sensitive channel, and mutations
in trp-4 cause locomotor defects (202).
Phototransduction. Given that phototransduction
in mammalian rods and cones
operates through closure of a cGMP-gated
channel, it is curious that Drosophila phototransduction
utilizes TRP channels. Recent
studies suggest that TRP channels may function
in a small subset of mammalian retinal
ganglion cells, which are photosensitive
(pRGCs) and contribute to circadian rhythm
(reviewed in 203). These pRGCs utilize a
phototransduction cascade that bears intriguing
similarities to Drosophila phototransduction.
The cascade initiates with light activation
of an opsin, melanopsin, and culminates
with depolarization of the cells. Heterologous
expression studies indicate that light activation
of melanopsin operates through a PLC
and TRPC3 (204–206); however, it is unclear
which TRP channel is coupled to the lightactivated
cascade in the pRGCs. Nevertheless,
the cascades functioning in pRGCs and
Drosophila photoreceptor cells appear to have
a common origin.
Sensing the Local Cellular
Environment
In addition to sensing stimuli from the external
environment, TRP channels enable cells
to respond to cues in their local environment.
TRPC channels in growth cone guidance,
neurite outgrowth, and synaptic activity.
TRP channels play roles during neurite outgrowth
and growth cone guidance in the developing
nervous system. Among the known
guidance cues are netrins and BDNF, which
exert either attractive or repulsive effects on
growth cones through the induction of Ca2+
influx. TRPC3 was a candidate for regulation
of growth cone guidance by BDNF because
it is activated in the developing mammalian
brain by BDNF (49). In support of this
possibility, knockdown of TRPC3 expression
with siRNAs inhibits BDNF-induced turning
of growth cones in cultured cerebellar
granule cells (207). Similarly, reduction in expression
of the Xenopus TRPC1 using morpholinos
interferes with growth cone turning
in response to either netrin-1 or BDNF
(208, 209). Another TRP channel, TRPC5,
operates in neurite extension, as exposure of
hippocampal neurons to EGF promotes the
plasma membrane insertion of TRPC5, which
inhibits neurite outgrowth (210).
TRPC channels function postsynaptically
in response to the activation of metabotropic
receptors. Activation of metabotropic
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serotonin receptors in the dendrites of
thalamic interneurons leads to release of the
neurotransmitter GABA (γ-aminobutyric
acid) from the dendrites and local GABAergic
inhibition. In neurons obtained from
TRPC4−/−
knockout animals, the dendritic
release of GABA is greatly reduced in thalamic
interneurons (211). In contrast to this
inhibitory role, TRPC1 appears to underlie
an excitatory postsynaptic current, following
activation of metabotropic glutamate receptors
in Purkinje cells, because manipulations
that interfere with TRPC1 activity reduce
the excitatory postsynaptic current (175).
Vascular tone. Influx of Ca2+
into vascular
endothelial cells causes the release of vasoactive
agents, which in turn induces Ca2+
influx
in smooth muscle cells and affects vascular
tone and blood pressure. Many TRP
channels are expressed in the endothelium
and have been implicated in endothelial function,
although the strongest genetic evidence
has been provided for TRPC4. Mice lacking
TRPC4 are deficient for an IP3-induced Ca2+
influx current and display greatly reduced vasorelaxation
(212). Elimination of TRPC6 increases
vascular smooth muscle contractility
and blood pressure (213). Paradoxically, there
is an increase in basal cation influx. This latter
effect results from increased expression
of TRPC3, which in the absence of TRPC6
shows constitutive activity. These latter results
are consistent with the evidence that
TRPC6 and TRPC3 form heteromultimers
(43) and suggest that TRPC3 is constitutively
active in the absence of TRPC6. This result is
reminiscent of the suppression of constitutive
activity of Drosophila TRPL, by interactions
with TRP (18).
Secretion of fluids and hormones. TRP
channels play important roles in the secretion
of fluids, electrolytes, and hormones in vertebrates
and invertebrates. In addition to functioning
during phototransduction, TRPL is
required for Ca2+
-mediated fluid transport in
a Drosophila epithelium (214). In mammals,
TRPC1 may play a role in fluid secretion as
it is expressed in human salivary gland cells
and its level of expression is correlated with
Ca2+
entry and fluid secretion in these cells
(215).
Two TRPM channels are implicated in insulin
secretion. TRPM4 is expressed in an
insulin pancreatic β-cell line, and expression
of a dominant negative form of this channel
reduces glucose-induced insulin secretion
(216). TRPM2 is also expressed in insulinproducing
pancreatic β-cells, and TRPM2
siRNAs decrease insulin secretion (217). The
activation of TRPM2 in these cells is proposed
to require both cyclic ADP–ribose and
37◦
C because the channel is poorly activated
by cyclic ADP–ribose at 25◦
C. Therefore,
TRPM2 is an additional example of chemical
and thermal inputs converging on a TRP
channel.
Kidney, urinary bladder, and bone function.
At least one TRP is required for urinary
bladder function as mutations in TRPV1
result in an increase in urinary bladder capacity
and inefficient voiding (218). Urothelial
cells from the TRPV1−/−
animals show a
defect in stretch-induced ATP release, which
may underlie the bladder phenotype because
purinergic signaling has been linked to bladder
function. It is not known whether TRPV1
is a mechanosensitive channel or whether it is
responding indirectly to membrane stretch.
Definitive evidence that TRP channels are
required for renal function in humans is that
mutations in TRP channels underlie kidney
diseases (see the following section below).
Elimination of mouse TRPV5 causes the animals
to excrete high levels of Ca2+
into the
urine, owing to a defect in Ca2+
reabsorption
along the kidney’s distal convolution, which is
the site of TRPV5 expression (219). TRPV5
is also expressed in osteoclasts, and TRPV5−/−
animals show a defect in transcellular Ca2+
transport during osteoclastic bone resorption
(220). The critical role for TRPV5 in these
processes is consistent with the observation
that TRPV5 and the highly related TRPV6
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are the most Ca2+
-selective channels among
the mammalian TRPs (1).
In the zebrafish, loss-of-function mutations
in TRPM7 result in dwarfism,
skeletal abnormalities, kidney stone formation,
melanophore development, and touchresponse
defects (221). In addition, there is
mineralization in the mesonephric tubules
and changes in ossification. TRPM7 is permeable
to Mg2+
and Ca2+
(99), and supplementation
with either Mg2+
or Ca2+
partially
rescues the melanophore-development phenotype,
whereas supplementation with Ca2+
partially restores the touch responsiveness. In
certain cell types, TRPM7 is essential for viability,
as deletion of TRPM7 in the chicken
DT-40 cell line results in cell lethality (99).
This phenotype results from a defect in Mg2+
homeostasis, as the addition of Mg2+
to the
media rescues the lethality (105).
TRP CHANNELS AND DISEASE
Four diseases have been shown to be caused by
mutations in TRP channels, and preliminary
data indicate that disruptions in TRP channels
underlie many additional diseases. Uncontrolled
activity of TRP channels may also
have pathological consequences and cause
neurodegeneration due to oxidative stress.
Hypomagnesemia and Hypocalcemia
Owing to Mutations in TRPM6
TRPM proteins are critical for Mg2+
uptake
in organisms ranging from worms to
humans. TRPM6 is expressed in the intestinal
brush border and in the renal convoluted
tubule, where it is required for Mg2+
absorption
(101). Of particular significance, mutations
in the TRPM6 chanzyme result in hypomagnesemia
with secondary hypocalcemia
(13, 14).
A role for TRPM proteins in Mg2+
homeostasis
is evolutionarily conserved. Two of the
four trpm genes in worms are expressed in
the intestines, and the inability of gon-2;gtl-1
mutants to reach adulthood is suppressed by
Mg2+
supplementation (222). Furthermore,
the gon-2;gtl-1 animals display increased tolerance
to Ni2+
toxicity (222), reminiscent of
the findings that TRPM7 is permeable to
Ni2+
and other trace metals (99).
TRPC6, Podocyte Function,
and Kidney Disease
Mutations in TRPC6 cause one type of kidney
disorder, focal and segmental glomerulosclerosis
(FSGS), which is characterized by
a breach in the capillary/kidney permeability
barrier and progression to end-stage renal disease
(11, 12). A critical structure contributing
to the filtration system in the kidney glomerulus
is the series of interdigitated foot processes
extending from the podocytes and surrounding
the capillaries. The slit diaphragm,
situated between the foot processes, forms
a multiprotein barrier that allows the passage
of small molecules from the capillaries
to the glomerulus. Disruption of this permeability
barrier, due to mutation of TRPC6,
can lead to proteinuria and end-stage renal
disease. TRPC6 has been proposed to be an
essential channel in the slit diaphragm because
it is localized in the foot processes,
near the slit diaphragm, and directly interacts
with two proteins, nephron and podocin,
known to be situated in these regions. FSGS
patients also display hypertension, which is a
clinical manifestation consistent with higher
blood pressure in the TRPC6-knockout mice
(213). Whether older TRPC6−/−
mice display
kidney defects remains to be reported.
The mechanism of TRPC6 activation in
the podocytes is also unresolved; given the
mechanosensitivity of these cells, TRPC6
may be mechanically gated in podocytes.
TRPPs and Autosomal Dominant
Polycystic Kidney Disease
ADPKD is the most common disease worldwide
of monogenic origin and results from
mutations either in the channel TRPP2 or the
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associated protein TRPP1 (reviewed in 223).
The hallmark of this disorder is renal cysts
and kidney failure, although this is a systemic
disease, which can affect many tissues. The
patients are heterozygous for the initial mutation
in either TRPP1 or TRPP2, and the
disease results from a somatic mutation in the
second copy of the gene.
The normal functions of TRPP proteins
remain poorly understood; however, a key insight
is that the TRPP2 and TRPP1 tend
to be localized in axonemal structures, such
as monocilia (224). These cilia are small appendages
that extend from most cells and are
capable of sensing shear stress during fluid
flow. TRPP2 is also expressed in the motile
node cell monocilia (148, 225), which is critical
in establishing left-right asymmetry during
embryogenesis by generating fluid flow.
Cells from TRPP2−/−
embryos exhibit laterality
defects and do not display the Ca2+
rise
in the node cilia, which is induced in wildtype
embryos upon fluid flow over the cilia
(148, 225). Thus TRPP2 may function as a
mechanosensor, which detects the shear force
resulting from fluid flow (147).
Specialized axonemal structures related to
monocilia include mechanosensors, the outer
segments of mammalian photoreceptor cells,
and sperm. In support of an evolutionarily
conserved role for TRPPs in axonemal structures,
worm TRPPs are concentrated in sensory
cilia and function in male sensory behavior
(137). The Drosophila TRPP2 AMO
is localized to the sperm tail (139) and is essential
for entry in the female storage organs
(138, 139).
TRPML1 and Mucolipidosis Type IV
MLIV is a severe neurodegenerative disorder,
which arises from mutations in TRPML1 (7–
9). The clinical manifestations typically become
evident by the time children are two to
three years old of age and include neurodegeneration,
mental retardation, achlorhydria,
and retinal degeneration. MLIV is primarily a
lysosomal storage disorder, and as is typical of
other lysosomal storage disorders, cells from
patients with MLIV contain many large vesicles
and accumulate lysosomal storage components,
such as phospholipids, mucopolysaccharides,
and gangliosides (226). There does
not appear to be a defect in lysosomal enzymes,
and the specific role for TRPML1 is
not known. TRPML1 may be required for
lysosomal reformation/biogenesis (227), and
this model is supported by analyses of worms
harboring a mutation in cup-5, the C. elegans
homolog of TRPML1 (228).
Oxidative Stress, Constitutively
Active TRPs, and Neuronal
Cell Death
Hypoxia can lead to excessive Ca2+
influx and
cell death owing to Ca2+
overload. Such a
phenomenon is of particular importance in
the brain, where oxidative stress leads to neuronal
cell death following stroke and certain
chronic neurodegenerative diseases. There
is accumulating evidence that TRP channels
contribute significantly to neuronal cell
death under anoxic conditions, although the
first demonstration that oxidative stress causes
constitutive activity of a TRP was obtained
for TRPC3 in aortic endothelial cells (229).
Drosophila TRP and TRPL are activated in
vivo following application of mitochondrial
uncouplers (230), and mutations that cause
constitutive activation of TRP result in massive
photoreceptor cell death (231). Evidence
that this death indeed results from Ca2+
overload
is that the retinal degeneration is suppressed
by overexpression of the Na+
/Ca2+
exchanger (232).
Two mediators of hypoxia-induced neuronal
cell death in the mammalian brain
appear to be TRPM2 and TRPM7. Cells
heterologously expressing TRPM2 display
an increased susceptibility to cell death
following exposure to reactive oxygen species
(110). Moreover, inhibition of native TRPM2
expression in a rat insulinoma cell line and
in cultured cortical neurons reduces H2O2induced
cell death (110, 233). Expression of a
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ANRV313-BI76-17 ARI 8 May 2007 21:51
naturally occurring truncated form of
TRPM2 decreased the sensitivity to cell
death owing to oxidative stress (114). In a
related model for neuronal cell death induced
by oxygen glucose deprivation, suppression
of native TRPM7 expression inhibited
cell death in cortical neuronal cultures
(234).
The concept that TRP channels are activated
under hypoxic conditions does not apply
only to pathological conditions, such as during
ischemia and in some chronic neurological
diseases, but also most likely reflects a physiological
role for TRP channels. In the worm,
O2 levels affect multiple behaviors, and two
TRPV channels (OSM-9 and OCR-2) are required
for the avoidance of high O2 (235). The
effects of O2 on OSM-9 or OCR-2 activity are
not known.
FUTURE PERSPECTIVES
Based on an array of highly suggestive studies
that are not reviewed here owing to space limitations,
it is likely that many more diseases will
be shown to result from mutations or changes
in the activities of TRP channels. These include
cardiovascular diseases, sensory deficits,
abnormal sensitivities to pain, gastrointestinal
diseases, additional renal and neurodegenerative
diseases, certain cancers, asthma,
and even psychiatric diseases. Consistent with
this last possibility is the association of alterations
in TRPM2 with bipolar disorder (236,
237). Finally, TRP channels are exciting targets
for drug development. Inhibitors of TRP
channels hold the potential for the control of
pain, asthma, and neurodegenerative diseases,
which are associated with increased activities
of TRP channels.
ACKNOWLEDGMENT
Work in the laboratory of C.M. is supported by the NEI, NIDCD, and the March of Dimes.
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Annual Review of
Biochemistry
Volume 76, 2007Contents
Mitochondrial Theme
The Magic Garden
Gottfried Schatz p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p673
DNA Replication and Transcription in Mammalian Mitochondria
Maria Falkenberg, Nils-Göran Larsson, and Claes M. Gustafsson p p p p p p p p p p p p p p p p p p p679
Mitochondrial-Nuclear Communications
Michael T. Ryan and Nicholas J. Hoogenraad p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p701
Translocation of Proteins into Mitochondria
Walter Neupert and Johannes M. Herrmann p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p723
The Machines that Divide and Fuse Mitochondria
Suzanne Hoppins, Laura Lackner, and Jodi Nunnari p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p751
Why Do We Still Have a Maternally Inherited Mitochondrial DNA?
Insights from Evolutionary Medicine
Douglas C. Wallace p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p781
Molecular Mechanisms of Antibody Somatic Hypermutation
Javier M. Di Noia and Michael S. Neuberger p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p1
Structure and Mechanism of Helicases and Nucleic Acid Translocases
Martin R. Singleton, Mark S. Dillingham, and Dale B. Wigley p p p p p p p p p p p p p p p p p p p p p p 23
The Nonsense-Mediated Decay RNA Surveillance Pathway
Yao-Fu Chang, J. Saadi Imam, Miles F. Wilkinson p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 51
Functions of Site-Specific Histone Acetylation and Deacetylation
Mona D. Shahbazian and Michael Grunstein p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 75
The tmRNA System for Translational Surveillance and Ribosome Rescue
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Membrane Protein Structure: Prediction versus Reality
Arne Elofsson and Gunnar von Heijne p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p125
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Structure and Function of Toll Receptors and Their Ligands
Nicholas J. Gay and Monique Gangloff p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p141
The Role of Mass Spectrometry in Structure Elucidation of Dynamic
Protein Complexes
Michal Sharon and Carol V. Robinson p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p167
Structure and Mechanism of the 6-Deoxyerythronolide B Synthase
Chaitan Khosla, Yinyan Tang, Alice Y. Chen, Nathan A. Schnarr,
and David E. Cane p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p195
The Biochemistry of Methane Oxidation
Amanda S. Hakemian and Amy C. Rosenzweig p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p223
Anthrax Toxin: Receptor Binding, Internalization, Pore Formation,
and Translocation
John A.T. Young and R. John Collier p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p243
Synapses: Sites of Cell Recognition, Adhesion, and Functional
Specification
Soichiro Yamada and W. James Nelson p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p267
Lipid A Modification Systems in Gram-negative Bacteria
Christian R.H. Raetz, C. Michael Reynolds, M. Stephen Trent,
and Russell E. Bishop p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p295
Chemical Evolution as a Tool for Molecular Discovery
S. Jarrett Wrenn and Pehr B. Harbury p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p331
Molecular Mechanisms of Magnetosome Formation
Arash Komeili p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p351
Modulation of the Ryanodine Receptor and Intracellular Calcium
Ran Zalk, Stephan E. Lehnart, and Andrew R. Marks p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p367
TRP Channels
Kartik Venkatachalam and Craig Montell p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p387
Studying Individual Events in Biology
Stefan Wennmalm and Sanford M. Simon p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p419
Signaling Pathways Downstream of Pattern-Recognition Receptors
and Their Cross Talk
Myeong Sup Lee and Young-Joon Kim p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p447
Biochemistry and Physiology of Cyclic Nucleotide Phosphodiesterases:
Essential Components in Cyclic Nucleotide Signaling
Marco Conti and Joseph Beavo p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p481
The Eyes Absent Family of Phosphotyrosine Phosphatases: Properties
and Roles in Developmental Regulation of Transcription
Jennifer Jemc and Ilaria Rebay p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p513
vi Contents
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Assembly Dynamics of the Bacterial MinCDE System and Spatial
Regulation of the Z Ring
Joe Lutkenhaus p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p539
Structures and Functions of Yeast Kinetochore Complexes
Stefan Westermann, David G. Drubin, and Georjana Barnes p p p p p p p p p p p p p p p p p p p p p p p p563
Mechanism and Function of Formins in the Control of Actin Assembly
Bruce L. Goode and Michael J. Eck p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p593
Unsolved Mysteries in Membrane Traffic
Suzanne R. Pfeffer p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p629
Structural Biology of Nucleocytoplasmic Transport
Atlanta Cook, Fulvia Bono, Martin Jinek, and Elena Conti p p p p p p p p p p p p p p p p p p p p p p p p p p647
The Postsynaptic Architecture of Excitatory Synapses: A More
Quantitative View
Morgan Sheng and Casper C. Hoogenraad p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p823
Indexes
Cumulative Index of Contributing Authors, Volumes 72–76 p p p p p p p p p p p p p p p p p p p p p p p p849
Cumulative Index of Chapter Titles, Volumes 72–76 p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p853
Errata
An online log of corrections to Annual Review of Biochemistry chapters (if any, 1997
to the present) may be found at http://biochem.annualreviews.org/errata.shtml
Contents vii
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