|Transient receptor potential (TRP) ion channel|
Transient receptor potential channels (TRP channels) are a group of ion channels located mostly on the plasma membrane of numerous animal cell types. There are about 30 TRP channels that share some structural similarity to each other. These are grouped into two broad groups: Group 1 includes TRPC ( "C" for canonical), TRPV ("V" for vanilloid), TRPM ("M" for melastatin), TRPN ("N" for no mechanoreceptor potential C) , and TRPA ("A" for ankyrin). In group 2, there are TRPP ("P" for polycystic) and TRPML ("ML" for mucolipin). 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), chili pepper (capsaicin), wasabi (allyl isothiocyanate); others are activated by menthol, camphor, peppermint, and cooling agents; yet others are activated by molecules found in cannabis (i.e., THC, CBD and CBN) or stevia. Some act as sensors of osmotic pressure, volume, stretch, and vibration.
These ion channels have a relatively non-selective permeability to cations, including sodium, calcium and magnesium. TRP channels were initially discovered in trp-mutant strain of the fruit fly Drosophila. 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. Mammalian TRP channels are activated and regulated by a wide variety of stimuli and are expressed throughout the body.
In the TRP super-family there are currently 7 different sub-families split into two groups. Group one consists of TRPC, TRPV, TRPA, TRPM, and TRPN. While group two contains TRPP and TRPML. There is an eighth sub-family labeled TRPY that is not included in either of these groups because of its distant relation. 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 a C-terminal, intracellular ankyrin repeat sequence, an N-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:
|TRPC1||Ubiquitous; heart, brain, testis, ovary, liver, spleen||1|
|TRPC2||Vomeronasal organ (VNO), testis|
|TRPC3||Central Nervous System (CNS), cardiac and smooth muscle|
|TRPC4||CNS, placenta, adrenal gland, endothelium, retina, smooth muscle, testis, kidney, interstitial cells of Cajal|
|TRPC5||CNS (especially developing fetal brain)|
|TRPC6||Lung, brain, placenta, ovary, kidney (podocytes), spleen, small intestine, neutrophils, smooth muscle|
|TRPC7||Heart, lung, eye, pituitary gland|
TRPC, C for "canonical", is named for being the most closely related to TRP channels in drosophilia, sharing above 30% amino acid homology. 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 in the kidneys. All TRPC channels are activated either by phospholipase C (PLC) or diacyglycerol (DAG).
|TRPV1||Dorsal root ganglia (DRG), trigeminal ganglia (TG), brain, peripheral nerve ends, skin, bladder, pancreas, testis||1|
|TRPV2||DRG, CNS, GI-tract, spleen, mast cells, smooth, cardiac, and skeletal muscle cells|
|TRPV3||DRG, TG, CNS, skin, tongue, testis, hair follicles|
|TRPV4||CNS, DRG, TG, kidney, lung, spleen, heart, liver, skin, endothelium, testis, bladder, cochlea, osteoblasts|
|TRPV5||Kidney, GI-tract, pancreas, placenta, testis, prostate, brain, salivary glands|
|TRPV6||GI-tract, kidney, pancreas, placenta, testis, prostate, brain, salivary glands|
TRPV, V for "vanilloid", is named for the vanilloid chemicals that activate this channel, and are some of the most studied TRP channels. These channels have been made famous for their association with molecules such as capsaicin (a TRPV1 agonist), and its ability to produce heat sensation and act as a topical ointment for pain relief.
|TRPA1||DRG, TG, hair cells, fibroblasts, ovary, spleen, testis||1|
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.
|TRPM1||Melanocytes, retina, brain||1|
|TRPM2||Brain, bone marrow, neutrophils, lung, spleen, eye, heart, liver|
|TRPM3||Kidney, CNS, pituitary, testis, ovary, pancreas, sensory neurons|
|TRPM4||Heart, pancreas, prostate, testis, colon, macula densa (kidney), lung, placenta, smooth muscle|
|TRPM5||Tongue, GI-tract, liver, lung, testis, brain, pancreas|
|TRPM7||Kidney, bone, heart, pituitary, adipose|
|TRPM8||DRG, TG, liver, smooth muscle, stomach, bladder, prostate|
TRPM, M for "melastatin", was found during a comparative genetic analysis between benign nevi and malignant nevi (melanoma). Mutatations within TRPM channels have been associated with hypomagnesemia with secondary hypocalcemia. TRPM channels have also become famous for their cold-sensing mechanisms, such is the case with TRPM8.
TRPN, N for "no mechanoreceptor potential C" or "NOMPC", are not found in mammals and have been shown only to be expressed in zebrafish, worms, and flies. There is more to be discovered as to what TRPN does, however, it is thought to be mechanically gated.
|TRPP2||Ubiquitous; kidney, ovary, testis, small intestine||2|
|TRPP3||Heart, skeletal muscle, kidney, spleen, retina, liver, testis, brain|
|TRPP5||Testis, heart, kidney, brain|
|TRPML1||Brain, heart, skeletal muscle,||2|
|TRPML2||Intracellular ion channel|
TRPML, ML for "mucolipin", gets its name from the neurodevelopmental disorder mucolipidosis IV. 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.
TRPY1, 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.
TRP channels are composed of 6 membrane-spanning helices (S1-S6) with intracellular N- and C-termini. Mammalian TRP channels are activated and regulated by a wide variety of stimuli including many post-transcriptional mechanisms like phosphorylation, G-protein receptor coupling, ligand-gating, and ubiquitination. 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.
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 mulitmerization. Other C-terminal modifications such as alpha-kinase domains in TRPM7 and M8 have been seen as well in this group.
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.
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  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, volume, stretch, and vibration. TRPs have been seen to have complex multidimensional roles in sensory signaling. Many TRPs function as intracellular calcium release channels.
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 relates to mechanisms of sensing cold, TRPV1 and TRPM3 contribute to heat and inflammation sensations, and TRPA1 facilitates many signaling pathways like sensory transduction, nociception, inflammation and oxidative stress.
TRPM5 is involved in taste signaling of sweet, bitter and umami tastes by modulating the signal pathway in type II taste receptor cells.. TRPM5 is activated by the sweet glycosides found in the stevia 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), wasabi, and cinnamon, TRPA1 and TRPV1 responds to garlic (allicin), TRPV1 responds to chilli pepper (capsaicin), TRPM8 is activated by menthol, camphor, peppermint, and cooling agents; TRPV2 is activated by molecules (THC, CBD and CBN) found in marijuana.
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 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 synapses with second-order retinal neurons 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 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.
Mutations in TRPs have been linked to neurodegenerative disorders, skeletal dysplasia, 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 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
Altered expression of TRP proteins often leads to tumorigenesis, 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 or Golgi apparatus 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 in clear cell renal cell carcinoma, TRPM4 is overexpressed in diffuse large B-cell lymphoma associated with poorer survival, while TRPM5 has oncogenic properties in melanoma.
In addition to TLR4 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.
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 ERG response to light and 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.