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Transient receptor potential channels (TRP channels) are a group of
ion channel Ion channels are pore-forming membrane proteins that allow ions to pass through the channel pore. Their functions include establishing a resting membrane potential, shaping action potentials and other electrical signals by gating the flow of ...
s located mostly on the
plasma membrane The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment (t ...
of numerous animal cell types. Most of these are grouped into two broad groups: Group 1 includes
TRPC TRPC is a family of transient receptor potential cation channels in animals. TRPC channels form the subfamily of channels in humans most closely related to drosophila TRP channels. Structurally, members of this family possess a number of similar ...
( "C" for canonical),
TRPV TRPV is a family of transient receptor potential cation channels (TRP channels) in animals. All TRPVs are highly calcium selective. TRP channels are a large group of ion channels consisting of six protein families, located mostly on the plasma ...
("V" for vanilloid), TRPVL ("VL" for vanilloid-like), TRPM ("M" for melastatin),
TRPS Tunable Resistive Pulse Sensing (TRPS) is a single-particle technique used to measure the size, concentration and zeta potential of particles as they pass through a size-tunable nanopore. The technique adapts the principle of resistive pulse sens ...
("S" for soromelastatin), TRPN ("N" for no mechanoreceptor potential C), and TRPA ("A" for ankyrin). Group 2 consists of
TRPP TRPP (transient receptor potential polycystic) is a family of transient receptor potential ion channels which when mutated can cause polycystic kidney disease. Subcategories TRPP subunits can be divided into two subcategories depending on structu ...
("P" for polycystic) and
TRPML TRPML (transient receptor potential cation channel, mucolipin subfamily) comprises a group of three evolutionarily related proteins that belongs to the large family of transient receptor potential ion channels. The three proteins TRPML1, TRPML2 ...
("ML" for mucolipin). Other less-well categorized TRP channels exist, including yeast channels and a number of Group 1 and Group 2 channels present in non-animals. Many of these channels mediate a variety of sensations such as pain, temperature, different kinds of tastes, pressure, and vision. In the body, some TRP channels are thought to behave like microscopic thermometers and used in animals to sense hot or cold. Some TRP channels are activated by molecules found in spices like garlic (
allicin Allicin is an organosulfur compound obtained from garlic, a species in the family Alliaceae. It was first isolated and studied in the laboratory by Chester J. Cavallito and John Hays Bailey in 1944. When fresh garlic is chopped or crushed, th ...
), chili pepper (
capsaicin Capsaicin (8-methyl-''N''-vanillyl-6-nonenamide) ( or ) is an active component of chili peppers, which are plants belonging to the genus ''Capsicum''. It is a chemical irritant for mammals, including humans, and produces a sensation of burnin ...
), wasabi (
allyl isothiocyanate Allyl isothiocyanate (AITC) is an organosulfur compound (formula CH2CHCH2NCS). This colorless oil is responsible for the pungent taste of mustard, radish, horseradish, and wasabi. This pungency and the lachrymatory effect of AITC are mediated thr ...
); others are activated by
menthol Menthol is an organic compound, more specifically a monoterpenoid, made synthetically or obtained from the oils of corn mint, peppermint, or other mints. It is a waxy, clear or white crystalline substance, which is solid at room temperature ...
,
camphor Camphor () is a waxy, colorless solid with a strong aroma. It is classified as a terpenoid and a cyclic ketone. It is found in the wood of the camphor laurel (''Cinnamomum camphora''), a large evergreen tree found in East Asia; and in the k ...
, peppermint, and cooling agents; yet others are activated by molecules found in
cannabis ''Cannabis'' () is a genus of flowering plants in the family Cannabaceae. The number of species within the genus is disputed. Three species may be recognized: '' Cannabis sativa'', '' C. indica'', and '' C. ruderalis''. Alternative ...
(i.e.,
THC Tetrahydrocannabinol (THC) is the principal psychoactive constituent of cannabis and one of at least 113 total cannabinoids identified on the plant. Although the chemical formula for THC (C21H30O2) describes multiple isomers, the term ''THC' ...
, CBD and CBN) or
stevia Stevia () is a natural sweetener and sugar substitute derived from the leaves of the plant species ''Stevia rebaudiana'', native to Paraguay and Brazil. The active compounds are steviol glycosides (mainly stevioside and rebaudioside), which ...
. Some act as sensors of osmotic pressure, volume, stretch, and vibration. Most of the channels are activated or inhibited by signaling lipids and contribute to a family of
lipid-gated ion channels Lipid-gated ion channels are a class of ion channels whose conductance of ions through the membrane depends directly on lipids. Classically the lipids are membrane resident anionic signaling lipids that bind to the transmembrane domain on the inn ...
. These
ion channel Ion channels are pore-forming membrane proteins that allow ions to pass through the channel pore. Their functions include establishing a resting membrane potential, shaping action potentials and other electrical signals by gating the flow of ...
s have a relatively non-selective permeability to
cation An ion () is an atom or molecule with a net electrical charge. The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by conven ...
s, including
sodium Sodium is a chemical element with the symbol Na (from Latin ''natrium'') and atomic number 11. It is a soft, silvery-white, highly reactive metal. Sodium is an alkali metal, being in group 1 of the periodic table. Its only stable ...
,
calcium Calcium is a chemical element with the symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar ...
and
magnesium Magnesium is a chemical element with the symbol Mg and atomic number 12. It is a shiny gray metal having a low density, low melting point and high chemical reactivity. Like the other alkaline earth metals (group 2 of the periodic ...
. TRP channels were initially discovered in the so-called "transient receptor potential" mutant (''trp''-mutant) strain of the fruit fly ''
Drosophila ''Drosophila'' () is a genus of flies, belonging to the family Drosophilidae, whose members are often called "small fruit flies" or (less frequently) pomace flies, vinegar flies, or wine flies, a reference to the characteristic of many speci ...
'', hence their name (see History of ''Drosophila'' TRP channels below). Later, TRP channels were found in vertebrates where they are ubiquitously expressed in many cell types and tissues. Most TRP channels are composed of 6 membrane-spanning helices with intracellular N- and
C-termini The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain ( protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein is ...
. Mammalian TRP channels are activated and regulated by a wide variety of stimuli and are expressed throughout the body.


Families

In the animal TRP superfamily there are currently 9 proposed families split into two groups, each family containing a number of subfamilies. Group one consists of TRPC, TRPV, TRPVL, TRPA, TRPM, TRPS, and TRPN, while group two contains TRPP and TRPML. There is an additional family labeled TRPY that is not always included in either of these groups. All of these sub-families are similar in that they are molecular sensing, non-selective cation channels that have six transmembrane segments, however, each sub-family is very unique and shares little structural homology with one another. This uniqueness gives rise to the various sensory perception and regulation functions that TRP channels have throughout the body. Group one and group two vary in that both TRPP and TRPML of group two have a much longer extracellular loop between the S1 and S2 transmembrane segments. Another differentiating characteristic is that all the group one sub-families either contain an N-terminal intracellular ankyrin repeat sequence, a C-terminal TRP domain sequence, or both—whereas both group two sub-families have neither. Below are members of the sub-families and a brief description of each:


TRPA

TRPA, A for "ankyrin", is named for the large amount of ankyrin repeats found near the N-terminus. TRPA is primarily found in afferent nociceptive nerve fibers and is associated with the amplification of pain signaling as well as cold pain hypersensitivity. These channels have been shown to be both mechanical receptors for pain and chemosensors activated by various chemical species, including isothiocyanates (pungent chemicals in substances such as mustard oil and wasabi), cannabinoids, general and local analgesics, and cinnamaldehyde. While TRPA1 is expressed in a wide variety of animals, a variety of other TRPA channels exist outside of vertebrates. TRPA5, painless, pyrexia, and waterwitch are distinct phylogenetic branches within the TRPA clade, and are only evidenced to be expressed in crustaceans and insects, while HsTRPA arose as a Hymenoptera-specific duplication of waterwitch. Like TRPA1 and other TRP channels, these function as ion channels in a number of sensory systems. TRPA- or TRPA1-like channels also exists in a variety of species as a phylogenetically distinct clade, but these are less well understood.


TRPC

TRPC, C for "canonical", is named for being the most closely related to Drosophila TRP, the namesake of TRP channels. The phylogeny of TRPC channels has not been resolved in detail, but they are present across animal taxa. There are actually only six TRPC channels expressed in humans because TRPC2 is found to be expressed solely in mice and is considered a pseudo-gene in humans; this is partly due to the role of TRPC2 in detecting pheromones, which mice have an increased ability compared to humans. Mutations in TRPC channels have been associated with respiratory diseases along with
focal segmental glomerulosclerosis Focal segmental glomerulosclerosis (FSGS) is a histopathologic finding of scarring (sclerosis) of glomeruli and damage to renal podocytes.Rosenberg, Avi Z.; Kopp, Jeffrey B. (2017-03-07). "Focal Segmental Glomerulosclerosis". ''Clinical Journal o ...
in the kidneys. All TRPC channels are activated either by
phospholipase C Phospholipase C (PLC) is a class of membrane-associated enzymes that cleave phospholipids just before the phosphate group (see figure). It is most commonly taken to be synonymous with the human forms of this enzyme, which play an important role ...
(PLC) or diacyglycerol (DAG).


TRPM

TRPM, M for "melastatin", was found during a comparative genetic analysis between benign
nevi Nevus (plural nevi) is a nonspecific medical term for a visible, circumscribed, chronic lesion of the skin or mucosa. The term originates from ''nævus'', which is Latin for "birthmark"; however, a nevus can be either congenital (present at bir ...
and malignant nevi (melanoma). Mutations within TRPM channels have been associated with hypomagnesemia with secondary hypocalcemia. TRPM channels have also become known for their cold-sensing mechanisms, such is the case with TRPM8. Comparative studies have shown that the functional domains and critical amino acids of TRPM channels are highly conserved across species.
Phylogenetics In biology, phylogenetics (; from Greek φυλή/ φῦλον [] "tribe, clan, race", and wikt:γενετικός, γενετικός [] "origin, source, birth") is the study of the evolutionary history and relationships among or within groups ...
has shown that TRPM channels are split into two major clades, αTRPM and βTRPM. αTRPMs include vertebrate TRPM1, TRPM3, and the "chanzymes" TRPM6 and TRPM7, as well as the only insect TRPM channel, among others. βTRPMs include, but are not limited to, vertebrate TRPM2, TRPM4, TRPM5, and TRPM8 (the cold and menthol sensor). Two additional major clades have been described: TRPMc, which is present only in a variety of arthropods, and a basal clade, which has since been proposed to be a distinct and separate TRP channel family (TRPS).


TRPML

TRPML, ML for "mucolipin", gets its name from the neurodevelopmental disorder
mucolipidosis IV Mucolipidosis type IV (ML IV, ganglioside sialidase deficiency, or ML4) is an autosomal recessive lysosomal storage disorder. Individuals with the disorder have many symptoms including delayed psychomotor development and various ocular aberrations ...
. Mucolipidosis IV was first discovered in 1974 by E.R. Berman who noticed abnormalities in the eyes of an infant. These abnormalities soon became associated with mutations to the MCOLN1 gene which encodes for the TRPML1 ion channel. TRPML is still not highly characterized. The three known vertebrate copies are restricted to jawed vertebrates, with some exceptions (e.g. ''
Xenopus tropicalis The western clawed frog (''Xenopus tropicalis'') is a species of frog in the family Pipidae, also known as tropical clawed frog. It is the only species in the genus ''Xenopus'' to have a diploid genome. Its genome has been sequenced, making it a ...
'').


TRPN

TRPN was originally described in ''Drosophila melanogaster'' and ''Caenorhabditis elegans'' as nompC, a mechanically gated ion channel. Only a single TRPN, N for "no mechanoreceptor potential C," or "nompC", is known to be broadly expressed in animals (although some Cnidarians have more), and is notably only a
pseudogene Pseudogenes are nonfunctional segments of DNA that resemble functional genes. Most arise as superfluous copies of functional genes, either directly by DNA duplication or indirectly by reverse transcription of an mRNA transcript. Pseudogenes ar ...
in
amniote Amniotes are a clade of tetrapod vertebrates that comprises sauropsids (including all reptiles and birds, and extinct parareptiles and non-avian dinosaurs) and synapsids (including pelycosaurs and therapsids such as mammals). They are dis ...
vertebrates. Despite TRPA being named for ankyrin repeats, TRPN channels are thought to have the most of any TRP channel, typically around 28, which are highly conserved across taxa Since its discovery, ''Drosophila'' nompC has been implicated in mechanosensation (including mechanical stimulation of the cuticle and sound detection) and cold
nociception Nociception (also nocioception, from Latin ''nocere'' 'to harm or hurt') is the Somatosensory system, sensory nervous system's process of encoding Noxious stimulus, noxious stimuli. It deals with a series of events and processes required for an org ...
.


TRPP

TRPP TRPP (transient receptor potential polycystic) is a family of transient receptor potential ion channels which when mutated can cause polycystic kidney disease. Subcategories TRPP subunits can be divided into two subcategories depending on structu ...
, P for "polycistin", is named for
polycystic kidney disease Polycystic kidney disease (PKD or PCKD, also known as polycystic kidney syndrome) is a genetic disorder in which the renal tubules become structurally abnormal, resulting in the development and growth of multiple cysts within the kidney. These c ...
, which is associated with these channels. These channels are also referred to as PKD (polycistic kindey disease) ion channels. PKD2-like genes (examples include TRPP2,
TRPP3 Polycystic kidney disease 2-like 2 protein (PKD2L2) also known as transient receptor potential polycystic 5 (TRPP5) is a protein that in humans is encoded by the ''PKD2L2'' gene. TRPP5 is a member of the transient receptor potential channel fami ...
, and TRPP5) encode canonical TRP channels. PKD1-like genes encode much larger proteins with 11 transmembrane segments, which do not have all the features of other TRP channels. However, 6 of the transmebrane segments of PKD1-like proteins have substantial sequence homology with TRP channels, indicating they may simply have diversified greatly from other closely related proteins. Insects have a third sub-family of TRPP, called brividos, which participate in cold sensing.


TRPS

TRPS, S for Soromelastatin, was named as it forms a sister group to TRPM. TRPS is broadly present in animals, but notably absent in vertebrates and insects (among others). TRPS has not yet been well described functionally, though it is known that the ''C. elegans'' TRPS, known as CED-11, is a calcium channel which participates in
apoptosis Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes ( morphology) and death. These changes in ...
.


TRPV

TRPV, V for "vanilloid", was originally discovered in ''Caenorhabditis elegans'', and is named for the vanilloid chemicals that activate some of these channels. These channels have been made famous for their association with molecules such as
capsaicin Capsaicin (8-methyl-''N''-vanillyl-6-nonenamide) ( or ) is an active component of chili peppers, which are plants belonging to the genus ''Capsicum''. It is a chemical irritant for mammals, including humans, and produces a sensation of burnin ...
(a TRPV1 agonist). In addition to the 6 known vertebrate paralogues, 2 major clades are known outside of the deterostomes: nanchung and Iav. Mechanistic studies of these latter clades have been largely restricted to ''Drosophila'', but phylogenetic analyses has placed a number of other genes from Placozoa, Annelida, Cnidaria, Mollusca, and other arthropods within them. TRPV channels have also been described in protists.


TRPVL

TRPVL has been proposed to be a sister clade to TRPV, and is limited to the cnidarians ''
Nematostella vectensis The starlet sea anemone (''Nematostella vectensis'') is a species of small sea anemone in the family Edwardsiidae native to the east coast of the United States, with introduced populations along the coast of southeast England and the west coast o ...
'' and '' Hydra magnipapillata'', and the annelid ''
Capitella teleta ''Capitella teleta'' is a small, cosmopolitan, segmented annelid worm. It is a well-studied invertebrate, which has been cultured for use in laboratories for over 30 years. ''C. teleta'' is the first marine polychaete to have its genome sequence ...
''. Little is known concerning these channels.


TRPY

TRPY, Y for "yeast", is highly localized to the yeast vacuole, which is the functional equivalent of a lysosome in a mammalian cell, and acts as a mechanosensor for vacuolar osmotic pressure. Patch clamp techniques and hyperosmotic stimulation have illustrated that TRPY plays a role in intracellular calcium release. Phylogenetic analysis has shown that TRPY1 does not form a part with the other metazoan TRP groups one and two, and is suggested to have evolved after the divergence of metazoans and fungi. Others have indicated that TRPY are more closely related to TRPP.


Structure

TRP channels are composed of 6
membrane A membrane is a selective barrier; it allows some things to pass through but stops others. Such things may be molecules, ions, or other small particles. Membranes can be generally classified into synthetic membranes and biological membranes. ...
-spanning helices (S1-S6) with intracellular N- and
C-termini The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain ( protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein is ...
. Mammalian TRP channels are activated and regulated by a wide variety of stimuli including many post-transcriptional mechanisms like
phosphorylation In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, wh ...
, G-protein receptor coupling, ligand-gating, and
ubiquitin Ubiquitin is a small (8.6 kDa) regulatory protein found in most tissues of eukaryotic organisms, i.e., it is found ''ubiquitously''. It was discovered in 1975 by Gideon Goldstein and further characterized throughout the late 1970s and 1980s. Fo ...
ation. The receptors are found in almost all cell types and are largely localized in cell and organelle membranes, modulating ion entry. Most TRP channels form homo- or heterotetramers when completely functional. The ion selectivity filter, pore, is formed by the complex combination of p-loops in the tetrameric protein, which are situated in the extracellular domain between the S5 and S6 transmembrane segments. As with most cation channels, TRP channels have negatively charged residues within the pore to attract the positively charged ions.


Group 1 Characteristics

Each channel in this group is structurally unique, which adds to the diversity of functions that TRP channels possess, however, there are some commonalities that distinguish this group from others. Starting from the intracellular N-terminus there are varying lengths of ankryin repeats (except in TRPM) that aid with membrane anchoring and other protein interactions. Shortly following S6 on the C-terminal end, there is a highly conserved TRP domain (except in TRPA) which is involved with gating modulation and channel multimerization. Other C-terminal modifications such as alpha-kinase domains in TRPM7 and M8 have been seen as well in this group.


Group 2 Characteristics

Group two most distinguishable trait is the long extracellular span between the S1 and S2 transmembrane segments. Members of group two are also lacking in ankryin repeats and a TRP domain. They have been shown, however, to have endoplasmic reticulum (ER) retention sequences towards on the C-terminal end illustrating possible interactions with the ER.


Function

TRP channels modulate ion entry driving forces and Ca2+ and Mg2+ transport machinery in the plasma membrane, where most of them are located. TRPs have important interactions with other proteins and often form signaling complexes, the exact pathways of which are unknown. TRP channels were initially discovered in the ''trp'' mutant strain of the fruit fly ''
Drosophila ''Drosophila'' () is a genus of flies, belonging to the family Drosophilidae, whose members are often called "small fruit flies" or (less frequently) pomace flies, vinegar flies, or wine flies, a reference to the characteristic of many speci ...
'' which displayed transient elevation of potential in response to light stimuli and were so named ''transient receptor potential'' channels. TRPML channels function as intracellular calcium release channels and thus serve an important role in organelle regulation. Importantly, many of these channels mediate a variety of sensations like the sensations of pain, temperature, different kinds of tastes, pressure, and vision. In the body, some TRP channels are thought to behave like microscopic thermometers and are used in animals to sense hot or cold. TRPs act as sensors of
osmotic pressure Osmotic pressure is the minimum pressure which needs to be applied to a solution to prevent the inward flow of its pure solvent across a semipermeable membrane. It is also defined as the measure of the tendency of a solution to take in a pure ...
,
volume Volume is a measure of occupied three-dimensional space. It is often quantified numerically using SI derived units (such as the cubic metre and litre) or by various imperial or US customary units (such as the gallon, quart, cubic inch). ...
, stretch, and
vibration Vibration is a mechanical phenomenon whereby oscillations occur about an equilibrium point. The word comes from Latin ''vibrationem'' ("shaking, brandishing"). The oscillations may be periodic, such as the motion of a pendulum—or random, su ...
. TRPs have been seen to have complex multidimensional roles in sensory signaling. Many TRPs function as intracellular calcium release channels.


Pain and temperature sensation

TRP ion channels convert energy into action potentials in somatosensory nociceptors. Thermo-TRP channels have a C-terminal domain that is responsible for thermosensation and have a specific interchangeable region that allows them to sense temperature stimuli that is tied to ligand regulatory processes. Although most TRP channels are modulated by changes in temperature, some have a crucial role in temperature sensation. There are at least 6 different Thermo-TRP channels and each plays a different role. For instance,
TRPM8 Transient receptor potential cation channel subfamily M (melastatin) member 8 (TRPM8), also known as the cold and menthol receptor 1 (CMR1), is a protein that in humans is encoded by the ''TRPM8'' gene. The TRPM8 channel is the primary molecular ...
relates to mechanisms of sensing cold,
TRPV1 The transient receptor potential cation channel subfamily V member 1 (TrpV1), also known as the capsaicin receptor and the vanilloid receptor 1, is a protein that, in humans, is encoded by the ''TRPV1'' gene. It was the first isolated member of th ...
and TRPM3 contribute to heat and inflammation sensations, and TRPA1 facilitates many signaling pathways like sensory transduction,
nociception Nociception (also nocioception, from Latin ''nocere'' 'to harm or hurt') is the Somatosensory system, sensory nervous system's process of encoding Noxious stimulus, noxious stimuli. It deals with a series of events and processes required for an org ...
,
inflammation Inflammation (from la, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants, and is a protective response involving immune cells, blood vessels, and molec ...
and
oxidative stress Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage. Disturbances in the normal ...
.


Taste

TRPM5 is involved in
taste The gustatory system or sense of taste is the sensory system that is partially responsible for the perception of taste (flavor). Taste is the perception produced or stimulated when a substance in the mouth reacts chemically with taste receptor ...
signaling of
sweet Sweetness is a basic taste most commonly perceived when eating foods rich in sugars. Sweet tastes are generally regarded as pleasurable. In addition to sugars like sucrose, many other chemical compounds are sweet, including aldehydes, ketone ...
, bitter and
umami Umami ( from ja, 旨味 ), or savoriness, is one of the five basic tastes. It has been described as savory and is characteristic of broths and cooked meats. People taste umami through taste receptors that typically respond to glutamates and ...
tastes by modulating the signal pathway in type II
taste receptor A taste receptor or tastant is a type of cellular receptor which facilitates the sensation of taste. When food or other substances enter the mouth, molecules interact with saliva and are bound to taste receptors in the oral cavity and other loc ...
cells. TRPM5 is activated by the sweet glycosides found in the
stevia Stevia () is a natural sweetener and sugar substitute derived from the leaves of the plant species ''Stevia rebaudiana'', native to Paraguay and Brazil. The active compounds are steviol glycosides (mainly stevioside and rebaudioside), which ...
plant. Several other TRP channels play a significant role in chemosensation through sensory nerve endings in the mouth that are independent from taste buds. TRPA1 responds to mustard oil (
allyl isothiocyanate Allyl isothiocyanate (AITC) is an organosulfur compound (formula CH2CHCH2NCS). This colorless oil is responsible for the pungent taste of mustard, radish, horseradish, and wasabi. This pungency and the lachrymatory effect of AITC are mediated thr ...
), wasabi, and cinnamon, TRPA1 and TRPV1 responds to garlic (
allicin Allicin is an organosulfur compound obtained from garlic, a species in the family Alliaceae. It was first isolated and studied in the laboratory by Chester J. Cavallito and John Hays Bailey in 1944. When fresh garlic is chopped or crushed, th ...
), TRPV1 responds to chilli pepper (
capsaicin Capsaicin (8-methyl-''N''-vanillyl-6-nonenamide) ( or ) is an active component of chili peppers, which are plants belonging to the genus ''Capsicum''. It is a chemical irritant for mammals, including humans, and produces a sensation of burnin ...
), TRPM8 is activated by
menthol Menthol is an organic compound, more specifically a monoterpenoid, made synthetically or obtained from the oils of corn mint, peppermint, or other mints. It is a waxy, clear or white crystalline substance, which is solid at room temperature ...
,
camphor Camphor () is a waxy, colorless solid with a strong aroma. It is classified as a terpenoid and a cyclic ketone. It is found in the wood of the camphor laurel (''Cinnamomum camphora''), a large evergreen tree found in East Asia; and in the k ...
,
peppermint Peppermint (''Mentha'' × ''piperita'') is a hybrid species of mint, a cross between watermint and spearmint. Indigenous to Europe and the Middle East, the plant is now widely spread and cultivated in many regions of the world.Euro+Med Plantb ...
, and cooling agents; TRPV2 is activated by molecules (
THC Tetrahydrocannabinol (THC) is the principal psychoactive constituent of cannabis and one of at least 113 total cannabinoids identified on the plant. Although the chemical formula for THC (C21H30O2) describes multiple isomers, the term ''THC' ...
, CBD and CBN) found in marijuana.


TRP-like channels in insect vision

The ''trp''-mutant fruit flies, which lack a functional copy of trp gene, are characterized by a transient response to light, unlike wild-type flies that demonstrate a sustained
photoreceptor cell A photoreceptor cell is a specialized type of neuroepithelial cell found in the retina that is capable of visual phototransduction. The great biological importance of photoreceptors is that they convert light (visible electromagnetic radiat ...
activity in response to light. A distantly related isoform of TRP channel, TRP-like channel (TRPL), was later identified in ''Drosophila'' photoreceptors, where it is expressed at approximately 10- to 20-fold lower levels than TRP protein. A mutant fly, ''trpl'', was subsequently isolated. Apart from structural differences, the TRP and TRPL channels differ in cation permeability and pharmacological properties. TRP/TRPL channels are solely responsible for depolarization of insect photoreceptor plasma membrane in response to light. When these channels open, they allow sodium and calcium to enter the cell down the concentration gradient, which depolarizes the membrane. Variations in light intensity affect the total number of open TRP/TRPL channels, and, therefore, the degree of membrane depolarization. These graded voltage responses propagate to photoreceptor
synapse In the nervous system, a synapse is a structure that permits a neuron (or nerve cell) to pass an electrical or chemical signal to another neuron or to the target effector cell. Synapses are essential to the transmission of nervous impulses from ...
s with second-order retinal
neuron A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa ...
s and further to the brain. It is important to note that the mechanism of insect photoreception is dramatically different from that in mammals. Excitation of rhodopsin in mammalian photoreceptors leads to the hyperpolarization of the receptor membrane but not to depolarization as in the insect eye. In ''Drosophila'' and, it is presumed, other insects, a phospholipase C (PLC)-mediated signaling cascade links photoexcitation of
rhodopsin Rhodopsin, also known as visual purple, is a protein encoded by the RHO gene and a G-protein-coupled receptor (GPCR). It is the opsin of the rod cells in the retina and a light-sensitive receptor protein that triggers visual phototransductio ...
to the opening of the TRP/TRPL channels. Although numerous activators of these channels such as phosphatidylinositol-4,5-bisphosphate (PIP2) and polyunsaturated fatty acids (PUFAs) were known for years, a key factor mediating chemical coupling between PLC and TRP/TRPL channels remained a mystery until recently. It was found that breakdown of a lipid product of PLC cascade, diacylglycerol (DAG), by the enzyme diacylglycerol lipase, generates PUFAs that can activate TRP channels, thus initiating membrane depolarization in response to light. This mechanism of TRP channel activation may be well-preserved among other cell types where these channels perform various functions.


Clinical significance

Mutations in TRPs have been linked to
neurodegenerative A neurodegenerative disease is caused by the progressive loss of structure or function of neurons, in the process known as neurodegeneration. Such neuronal damage may ultimately involve cell death. Neurodegenerative diseases include amyotrophic ...
disorders, skeletal
dysplasia Dysplasia is any of various types of abnormal growth or development of cells (microscopic scale) or organs ( macroscopic scale), and the abnormal histology or anatomical structure(s) resulting from such growth. Dysplasias on a mainly microscopi ...
, kidney disorders, and may play an important role in cancer. TRPs may make important therapeutic targets. There is significant clinical significance to TRPV1, TRPV2, TRPV3 and TRPM8’s role as thermoreceptors, and TRPV4 and TRPA1’s role as mechanoreceptors; reduction of chronic pain may be possible by targeting ion channels involved in thermal, chemical, and mechanical sensation to reduce their sensitivity to stimuli. For instance the use of TRPV1 agonists would potentially inhibit
nociception Nociception (also nocioception, from Latin ''nocere'' 'to harm or hurt') is the Somatosensory system, sensory nervous system's process of encoding Noxious stimulus, noxious stimuli. It deals with a series of events and processes required for an org ...
at TRPV1, particularly in pancreatic tissue where TRPV1 is highly expressed. The TRPV1 agonist capsaicin, found in chili peppers, has been indicated to relieve neuropathic pain. TRPV1 agonists inhibit nociception at TRPV1


Role in cancer

Altered expression of TRP proteins often leads to
tumorigenesis Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a cancer, whereby normal cells are transformed into cancer cells. The process is characterized by changes at the cellular, genetic, and epigenetic levels and abnor ...
, as reported for TRPV1, TRPV6, TRPC1, TRPC6, TRPM4, TRPM5, and TRPM8. TRPV1 and TRPV2 have been implicated in breast cancer. TRPV1 expression in aggregates found at
endoplasmic reticulum The endoplasmic reticulum (ER) is, in essence, the transportation system of the eukaryotic cell, and has many other important functions such as protein folding. It is a type of organelle made up of two subunits – rough endoplasmic reticulum ...
or
Golgi apparatus The Golgi apparatus (), also known as the Golgi complex, Golgi body, or simply the Golgi, is an organelle found in most eukaryotic cells. Part of the endomembrane system in the cytoplasm, it packages proteins into membrane-bound vesicles i ...
and/or surrounding these structures in breast cancer patients confer worse survival. TRPV2 is a potential biomarker and therapeutic target in triple negative breast cancer. TRPM family of ion channels are particularly associated with prostate cancer where TRPM2 (and its long noncoding RNA ''TRPM2-AS''), TRPM4, and TRPM8 are overexpressed in prostate cancer associated with more aggressive outcomes. TRPM3 has been shown to promote growth and
autophagy Autophagy (or autophagocytosis; from the Ancient Greek , , meaning "self-devouring" and , , meaning "hollow") is the natural, conserved degradation of the cell that removes unnecessary or dysfunctional components through a lysosome-dependent re ...
in clear cell renal cell carcinoma, TRPM4 is overexpressed in
diffuse large B-cell lymphoma Diffuse large B-cell lymphoma (DLBCL) is a cancer of B cells, a type of lymphocyte that is responsible for producing antibodies. It is the most common form of non-Hodgkin lymphoma among adults, with an annual incidence of 7–8 cases per 100,00 ...
associated with poorer survival, while TRPM5 has oncogenic properties in
melanoma Melanoma, also redundantly known as malignant melanoma, is a type of skin cancer that develops from the pigment-producing cells known as melanocytes. Melanomas typically occur in the skin, but may rarely occur in the mouth, intestines, or eye ( ...
.


Role in inflammatory responses

In addition to
TLR4 Toll-like receptor 4 is a protein that in humans is encoded by the ''TLR4'' gene. TLR4 is a transmembrane protein, member of the toll-like receptor family, which belongs to the pattern recognition receptor (PRR) family. Its activation leads to an ...
mediated pathways, certain members of the family of the transient receptor potential ion channels recognize LPS. LPS-mediated activation of TRPA1 was shown in mice and ''Drosophila melanogaster'' flies. At higher concentrations, LPS activates other members of the sensory TRP channel family as well, such as TRPV1, TRPM3 and to some extent TRPM8. LPS is recognized by TRPV4 on epithelial cells. TRPV4 activation by LPS was necessary and sufficient to induce nitric oxide production with a bactericidal effect.


History of ''Drosophila'' TRP channels

The original TRP-mutant in ''Drosophila'' was first described by Cosens and Manning in 1969 as "a mutant strain of ''D. melanogaster'' which, though behaving phototactically positive in a T-maze under low ambient light, is visually impaired and behaves as though blind". It also showed an abnormal
electroretinogram Electroretinography measures the electrical responses of various cell types in the retina, including the photoreceptors ( rods and cones), inner retinal cells ( bipolar and amacrine cells), and the ganglion cells. Electrodes are placed on th ...
response of photoreceptors to light which was transient rather than sustained as in the "wild type". It was investigated subsequently by Baruch Minke, a post-doc in the group of William Pak, and named TRP according to its behavior in the ERG. The identity of the mutated protein was unknown until it was cloned by Craig Montell, a post-doctoral researcher in Gerald Rubin's research group, in 1989, who noted its predicted structural relationship to channels known at the time and Roger Hardie and Baruch Minke who provided evidence in 1992 that it is an ion channel that opens in response to light stimulation. The TRPL channel was cloned and characterized in 1992 by the research group of Leonard Kelly. In 2013, Montell and his research group found that the TRPL (TRP-like) cation channel was a direct target for tastants in gustatory receptor neurons and could be reversibly down-regulated.


See also

*
Endocannabinoid system The endocannabinoid system (ECS) is a biological system composed of endocannabinoids, which are endogenous lipid-based retrograde neurotransmitters that bind to cannabinoid receptors (CBRs), and cannabinoid receptor proteins that are expressed ...
*
Transient receptor potential channel-interacting protein database Transient receptor potential channel-interacting protein database (TRIP) is a database of protein–protein interactions for the mammalian TRP channels. See also * Protein-protein interactions * TRP channels References * External links * ...
(2010)


References


External links

* * * * {{Authority control Membrane biology Ion channels Voltage-gated ion channels