TRPV
Encyclopedia
Ion channel
Ion channels are pore-forming proteins that help establish and control the small voltage gradient across the plasma membrane of cells by allowing the flow of ions down their electrochemical gradient. They are present in the membranes that surround all biological cells...
s. These channels are selective for calcium
Calcium
Calcium is the chemical element with the symbol Ca and atomic number 20. It has an atomic mass of 40.078 amu. Calcium is a soft gray alkaline earth metal, and is the fifth-most-abundant element by mass in the Earth's crust...
and magnesium
Magnesium
Magnesium is a chemical element with the symbol Mg, atomic number 12, and common oxidation number +2. It is an alkaline earth metal and the eighth most abundant element in the Earth's crust and ninth in the known universe as a whole...
over sodium
Sodium
Sodium is a chemical element with the symbol Na and atomic number 11. It is a soft, silvery-white, highly reactive metal and is a member of the alkali metals; its only stable isotope is 23Na. It is an abundant element that exists in numerous minerals, most commonly as sodium chloride...
ions. Like other members of the TRP superfamily, TRPV channels can be activated through seemingly disparate mechanisms. In vertebrates, several members of the family are sensitive to elevated temperature, making them thermoTRPs.
The first member of this family that was isolated, TRPV1
TRPV1
The transient receptor potential cation channel subfamily V member 1 ', also known as the capsaicin receptor and the vanilloid receptor 1, is a protein that, in humans, is encoded by the TRPV1 gene...
, is also sensitive to capsaicin
Capsaicin
Capsaicin 2CHCH=CH4CONHCH2C6H3-4--3- ) is the active component of chili peppers, which are plants belonging to the genus Capsicum. It is an irritant for mammals, including humans, and produces a sensation of burning in any tissue with which it comes into contact...
, the pungent ingredient in "hot" chili pepper
Chili pepper
Chili pepper is the fruit of plants from the genus Capsicum, members of the nightshade family, Solanaceae. The term in British English and in Australia, New Zealand, India, Malaysia and other Asian countries is just chilli without pepper.Chili peppers originated in the Americas...
s and accordingly TRPV1 is also sometimes referred to as the capsaicin or vanilloid receptor.
The number of TRPV channel variants differs between species. Worms have 5, flies only 2, mice and humans 6 distinct receptors. The TRPV receptors can also form heteromer
Heteromer
-Pharmacology:* Ligand-gated ion channels such as the nicotinic acetylcholine receptor and GABAA receptor are composed of five subunits arranged around a central pore that opens to allow ions to pass through. There are a large number of different subunits available, which can come together in a...
s that exhibit unique conductance and gating properties, further increasing their functional diversity.
Discovery
The first mammalian TRPV channel, named VR1 at the time, was cloned from a rat and characterized in the laboratory of David JuliusDavid Julius
David J. Julius is an American physiologist. He is a professor at the University of California, San Francisco, and won the 2010 Shaw Prize in life science and medicine....
at the UCSF
University of California, San Francisco
The University of California, San Francisco is one of the world's leading centers of health sciences research, patient care, and education. UCSF's medical, pharmacy, dentistry, nursing, and graduate schools are among the top health science professional schools in the world...
, and the results were published in the journal Nature
Nature (journal)
Nature, first published on 4 November 1869, is ranked the world's most cited interdisciplinary scientific journal by the Science Edition of the 2010 Journal Citation Reports...
in 1997. The homolog
Homology (biology)
Homology forms the basis of organization for comparative biology. In 1843, Richard Owen defined homology as "the same organ in different animals under every variety of form and function". Organs as different as a bat's wing, a seal's flipper, a cat's paw and a human hand have a common underlying...
gene of TRPV1 in C. elegans
Caenorhabditis elegans
Caenorhabditis elegans is a free-living, transparent nematode , about 1 mm in length, which lives in temperate soil environments. Research into the molecular and developmental biology of C. elegans was begun in 1974 by Sydney Brenner and it has since been used extensively as a model...
was independently discovered in the same year, and its protein OSM-9
OSM-9
OSM-9 also known as OSMotic avoidance abnormal family member 9 is a protein which in the nematode worm C. elegans is encoded by the osm-9 gene.- Function :...
characterized by another research group at UCSF led by Cornelia Bargmann
Cornelia Bargmann
Cornelia Isabella "Cori" Bargmann is an American neurobiologist. She is known for her work on the behavior in the C. elegans, particularly olfaction in the worm...
. These discoveries defined the first typical family beyond the classical TRPC
TRPC
TRPC is a family of transient receptor potential cation channels in animals.TRPC channels form the subfamily of channels in human most closely related to drosophila TRP channels. In terms of structure, this family possesses a number of similar characteristics...
channels. The 2nd mammalian TRPV channel was identified in 1999, also by Julius' group. By 2002, Bargmann's group had identified all currently known TRPV genes in C. elegans and D. melanogaster
Drosophila melanogaster
Drosophila melanogaster is a species of Diptera, or the order of flies, in the family Drosophilidae. The species is known generally as the common fruit fly or vinegar fly. Starting from Charles W...
. In the same year three research groups simultaneously identified TRPV3, and characterized its thermal sensitivity.
Structure
Functional TRPV ion channels are tetrameric in structure and are either homo-tetrameric (four identical subunits) or hetero-tetrameric (a total of four subunits selected from two or more types of subunits). The four subunits are symmetrically arranged around the ion conduction pore. Although the extent of heteromerization has been the subject of some debate, the most recent research in this area suggest that all four thermosensitive TRPVs (1-4) can form heteromers with each other. This result is in line with the general observation that TRP coassembly tends to occur between subunits with high sequence similarities. How TRP subunits recognize and interact with each other is still poorly understood.The TRPV channel monomer
Monomer
A monomer is an atom or a small molecule that may bind chemically to other monomers to form a polymer; the term "monomeric protein" may also be used to describe one of the proteins making up a multiprotein complex...
ic subunit components each contain six transmembrane (TM) domains
Protein domain
A protein domain is a part of protein sequence and structure that can evolve, function, and exist independently of the rest of the protein chain. Each domain forms a compact three-dimensional structure and often can be independently stable and folded. Many proteins consist of several structural...
(designated S1–S6) with a pore domain between the fifth (S5) and sixth (S6) segments. TRPV subunits contain three to five N-terminal ankyrin repeats.
Vertebrates
TRPV channels can be activated through a variety of mechanisms. TRPV1 to TRPV4 can act as thermometers on a molecular level. Interestingly, each of these channels has a different thermal threshold for activation: TRPV2 is activated at 52°C, TRPV1 at 43°C, TRPV3 at 33°C, and TRPV4 below 33°C when expressed in transfected permanent cell lines (HEK293 and CHO cells) and in frog oocytes. This has not been proven in sensory neurons where for example no correlation between TRPV2 and heat sensitivity could be shown. TRPV1 is essential for inflammatory thermal hyperalgesiaHyperalgesia
Hyperalgesia is an increased sensitivity to pain, which may be caused by damage to nociceptors or peripheral nerves. Temporary increased sensitivity to pain also occurs as part of sickness behavior, the evolved response to infection.-Types:...
. In addition to noxious heat, TRPV1
TRPV1
The transient receptor potential cation channel subfamily V member 1 ', also known as the capsaicin receptor and the vanilloid receptor 1, is a protein that, in humans, is encoded by the TRPV1 gene...
is activated by acidic pH, the inflammatory vanilloid compound capsaicin
Capsaicin
Capsaicin 2CHCH=CH4CONHCH2C6H3-4--3- ) is the active component of chili peppers, which are plants belonging to the genus Capsicum. It is an irritant for mammals, including humans, and produces a sensation of burning in any tissue with which it comes into contact...
, pungent substances present in black pepper (piperine
Piperine
Piperine is the alkaloid responsible for the pungency of black pepper and long pepper, along with chavicine . It has also been used in some forms of traditional medicine and as an insecticide. Piperine forms monoclinic needles, is slightly soluble in water and more so in alcohol, ether or...
) and garlic (allicin), the topical analgesic camphor
Camphor
Camphor is a waxy, white or transparent solid with a strong, aromatic odor. It is a terpenoid with the chemical formula C10H16O. It is found in wood of the camphor laurel , a large evergreen tree found in Asia and also of Dryobalanops aromatica, a giant of the Bornean forests...
, and the endocannabinoids anandamide
Anandamide
Anandamide, also known as N-arachidonoylethanolamide or AEA, is an endogenous cannabinoid neurotransmitter. The name is taken from the Sanskrit word ananda, which means "bliss, delight", and amide. It is synthesized from N-arachidonoyl phosphatidylethanolamine by multiple pathways...
and N-arachidonoyl-dopamine
N-arachidonoyl-dopamine
N-Arachidonoyl dopamine is an endocannabinoid which acts as an agonist of the CB1 receptor and the transient receptor potential V1 ion channel. Its discovery was described in 2002 by an academic research group from Italy and the USA. It was found in the brain of rats, with especially high...
. The other TRPV family members are insensitive to vanilloid compounds. TRPV3 is activated by essential oils from clove
Clove
Cloves are the aromatic dried flower buds of a tree in the family Myrtaceae. Cloves are native to the Maluku islands in Indonesia and used as a spice in cuisines all over the world...
(eugenol
Eugenol
Eugenol is a phenylpropene, an allyl chain-substituted guaiacol. Eugenol is a member of the phenylpropanoids class of chemical compounds. It is a clear to pale yellow oily liquid extracted from certain essential oils especially from clove oil, nutmeg, cinnamon, basil and bay leaf. It is slightly...
), thyme
Thyme
Thyme is a culinary and medicinal herb of the genus Thymus.-History:Ancient Egyptians used thyme for embalming. The ancient Greeks used it in their baths and burnt it as incense in their temples, believing it was a source of courage...
(thymol
Thymol
Thymol is a natural monoterpene phenol derivative of cymene, C10H14O, isomeric with carvacrol, found in oil of thyme, and extracted from Thymus vulgaris and various other kinds of plants as a white crystalline substance of a pleasant aromatic odor and strong antiseptic properties...
) and oregano
Oregano
Oregano – scientifically named Origanum vulgare by Carolus Linnaeus – is a common species of Origanum, a genus of the mint family . It is native to warm-temperate western and southwestern Eurasia and the Mediterranean region.Oregano is a perennial herb, growing from 20–80 cm tall,...
(carvacrol
Carvacrol
Carvacrol, or cymophenol, C6H3CH3, is a monoterpenoid phenol. It has a characteristic pungent, warm odor of oregano and a pizza-like taste.- Natural occurrence :...
). TRPV3 is highly expressed in the nose, which may explain why the odors of these plants are associated with a sensation of warmth. Like TRPV1, TRPV3 is also activated by camphor
Camphor
Camphor is a waxy, white or transparent solid with a strong, aromatic odor. It is a terpenoid with the chemical formula C10H16O. It is found in wood of the camphor laurel , a large evergreen tree found in Asia and also of Dryobalanops aromatica, a giant of the Bornean forests...
. TRPV4 can be activated by cell swelling caused by 5',6'-ep-oxyeicosatrienoic acid. As of 2008, a knockout mouse
Knockout mouse
A knockout mouse is a genetically engineered mouse in which researchers have inactivated, or "knocked out," an existing gene by replacing it or disrupting it with an artificial piece of DNA...
model for TRPV2 is not available, making it difficult to assess additional roles of this channel.
The group 2 TRPV5
TRPV5
Transient receptor potential cation channel subfamily V member 5 is a protein that in humans is encoded by the TRPV5 gene.TRPV5 is mainly expressed in kidney epithelial cells, where it plays an important role in the reabsorption of Ca2+.. Genetic deletion of TRPV5 in mice leads to Ca2+ loss in the...
and TRPV6
TRPV6
TRPV6 is a membrane calcium channel which is responsible for the first step in calcium absorption in the intestine. It was first named CAT1, or ECaC2, and has been described in the intestine in several species, including humans. It is located in the apical brush-border membrane of the intestinal...
are calcium entry channels responsible for calcium absorption in the kidney and intestine respectively. They were originally named ECaC and CAT1. and expression is regulated by the vitamin D receptor
Calcitriol receptor
The calcitriol receptor, also known as the vitamin D receptor and also known as NR1I1 , is a member of the nuclear receptor family of transcription factors...
(VDR) through the active metabolite calcitriol
Calcitriol
Calcitriol , also called 1,25-dihydroxycholecalciferol or 1,25-dihydroxyvitamin D3, is the hormonally active form of vitamin D with three hydroxyl groups...
.
The table below summarizes the functions and properties of the individual TRPV channel family members:
| group | channel | function | tissue distribution | Ca2+/Na+ selectivity |
heteromeric associated subunits | other associated proteins |
|---|---|---|---|---|---|---|
| 1 | TRPV1 TRPV1 The transient receptor potential cation channel subfamily V member 1 ', also known as the capsaicin receptor and the vanilloid receptor 1, is a protein that, in humans, is encoded by the TRPV1 gene... |
vanilloid (capsaicin) receptor and noxious thermosensor Thermoreceptor A thermoreceptor is a sensory receptor, or more accurately the receptive portion of a sensory neuron, that codes absolute and relative changes in temperature, primarily within the innocuous range... (43°C) |
CNS Central nervous system The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish... and PNS Peripheral nervous system The peripheral nervous system consists of the nerves and ganglia outside of the brain and spinal cord. The main function of the PNS is to connect the central nervous system to the limbs and organs. Unlike the CNS, the PNS is not protected by the bone of spine and skull, or by the blood–brain... |
9:1 | TRPV2, TRPV3 | calmodulin Calmodulin Calmodulin is a calcium-binding protein expressed in all eukaryotic cells... , PI3 kinase Phosphoinositide 3-kinase Phosphatidylinositol 3-kinases are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which in turn are involved in cancer. In response to lipopolysaccharide, PI3K phosphorylates p65, inducing... |
| TRPV2 TRPV2 Transient receptor potential cation channel subfamily V member 2 is a protein that in humans is encoded by the TRPV2 gene.- Function :This gene encodes an ion channel that is activated by high temperatures above 52 °C. The protein may be involved in transduction of high-temperature heat responses... |
osmo Osmoreceptor An osmoreceptor is a sensory receptor primarily found in the hypothalamus of most homeothermic organisms that detects changes in osmotic pressure. Osmoreceptors can be found in several structures, including the organum vasculosum of the lamina terminalis and the subfornical organ... - and noxious heat thermosensor (52°C) |
CNS, spleen and lung | 3:1 | TRPV1 | ||
| TRPV3 TRPV3 Transient receptor potential cation channel, subfamily V, member 3, also known as TRPV3, is a human gene encoding the protein of the same name.- Physiology of TRPV3 channel :... |
warmth sensor channel (33-39°C) | Skin, CNS and PNS | 12:1 | TRPV1 | ||
| TRPV4 TRPV4 Transient receptor potential cation channel subfamily V member 4 is a protein that in humans is encoded by the TRPV4 gene.This gene encodes TRPV4, a member of the OSM9-like transient receptor potential channel subfamily in the transient receptor potential superfamily of ion channels... |
osmo- and warmth sensor channel (27-34°C) | CNS and internal organs | 6:1 | aquaporin 5 AQP5 Aquaporin-5 is a protein that in humans is encoded by the AQP5 gene.- External links :... , calmodulin, pacsin 3 PACSIN3 Protein kinase C and casein kinase substrate in neurons protein 3 is an enzyme that in humans is encoded by the PACSIN3 gene.-Interactions:PACSIN3 has been shown to interact with PACSIN1 and PACSIN2.-Further reading:... |
||
| 2 | TRPV5 TRPV5 Transient receptor potential cation channel subfamily V member 5 is a protein that in humans is encoded by the TRPV5 gene.TRPV5 is mainly expressed in kidney epithelial cells, where it plays an important role in the reabsorption of Ca2+.. Genetic deletion of TRPV5 in mice leads to Ca2+ loss in the... |
calcium-selective TRP channel | intestine, kidney, placenta | 100:1 | TRPV6 | annexin II / S100A10 S100A10 S100-A10, also known as p11, is a protein that is encoded by the S100A10 gene in humans and the S100a10 gene in other species. S100-A10 is a member of the S100 family of proteins containing two EF-hand calcium-binding motifs. S100 proteins are localized in the cytoplasm and/or nucleus of a wide... , calmodulin |
| TRPV6 TRPV6 TRPV6 is a membrane calcium channel which is responsible for the first step in calcium absorption in the intestine. It was first named CAT1, or ECaC2, and has been described in the intestine in several species, including humans. It is located in the apical brush-border membrane of the intestinal... |
calcium-selective TRP channel | kidney, intestine | 130:1 | TRPV5 | annexin II / S100A10, calmodulin |
Nematodes
In C. elegans, the OSM-9 protein is localized to the AWA sensory cilia. The olfactory function of this protein is confirmed by the fact that osm-9 mutants have a near-complete defect in the functions of ciliated sensory neurons, called ASH neurons, that act as polymodal nociceptors. These neurons mediate behavioral avoidance of high osmolarity, mechanical stimuli, noxious odors, heavy metals, bitter substances like quinineQuinine
Quinine is a natural white crystalline alkaloid having antipyretic , antimalarial, analgesic , anti-inflammatory properties and a bitter taste. It is a stereoisomer of quinidine which, unlike quinine, is an anti-arrhythmic...
, and acid pH. Wild C. elegans is insensitive to capsaicin, but if it is genetically modified to express TRPV1 instead of osm-9, then its ASH nociceptor neurons make it avoid capsaicin.
Flies
In D. melanogaster, the two TRPV proteins Nan (Nanchung) and Iav (Inactive) play a key role in the auditorychordotonal neurons in Johnston's organ
Johnston's organ
Johnston's organ is a collection of sensory cells found in the pedicel of the antennae in the Class Insecta. Johnston's organ detects motion in the flagellum . It consists of over 200 scolopidia arrayed in a bowl shape, each of which contains a mechanosensory chordotonal neuron...
. Mutations in either of these genes render the fly deaf. A possible explanation for this interdependency is that the two proteins form heteromers in vivo and depend on each other for protein stability. The most intriguiging finding is that alterations to Iav (but not Nan) alters Drosophila's sensitivity to cocaine.
Genes
There are six human genes encoding TRPV ion channels divided into two groups based on sequence homology and functional similarity:- Group 1: TRPV1TRPV1The transient receptor potential cation channel subfamily V member 1 ', also known as the capsaicin receptor and the vanilloid receptor 1, is a protein that, in humans, is encoded by the TRPV1 gene...
, TRPV2TRPV2Transient receptor potential cation channel subfamily V member 2 is a protein that in humans is encoded by the TRPV2 gene.- Function :This gene encodes an ion channel that is activated by high temperatures above 52 °C. The protein may be involved in transduction of high-temperature heat responses...
, TRPV3TRPV3Transient receptor potential cation channel, subfamily V, member 3, also known as TRPV3, is a human gene encoding the protein of the same name.- Physiology of TRPV3 channel :...
, TRPV4TRPV4Transient receptor potential cation channel subfamily V member 4 is a protein that in humans is encoded by the TRPV4 gene.This gene encodes TRPV4, a member of the OSM9-like transient receptor potential channel subfamily in the transient receptor potential superfamily of ion channels... - Group 2: TRPV5TRPV5Transient receptor potential cation channel subfamily V member 5 is a protein that in humans is encoded by the TRPV5 gene.TRPV5 is mainly expressed in kidney epithelial cells, where it plays an important role in the reabsorption of Ca2+.. Genetic deletion of TRPV5 in mice leads to Ca2+ loss in the...
, TRPV6TRPV6TRPV6 is a membrane calcium channel which is responsible for the first step in calcium absorption in the intestine. It was first named CAT1, or ECaC2, and has been described in the intestine in several species, including humans. It is located in the apical brush-border membrane of the intestinal...
In C. elegans there are two groups of genes that encode TRPV channels. One group contains a single gene, osm-9. The second group contains four ocr genes (osm-9/capsaicin receptor related). In D. melanogaster there are only two genes, one related to osm-9, called inactive, and another related to the ocr genes, called nanchung. This observation suggest that the common ancestor of nematodes and files had at least one osm-9-like gene and at least one ocr-like gene.
As drug targets
Four TRPVs (TRPV1, TRPV2, TRPV3, and TRPV4) are expressed in afferentAfferent nerve
In the nervous system, afferent neurons , carry nerve impulses from receptors or sense organs towards the central nervous system. This term can also be used to describe relative connections between structures. Afferent neurons communicate with specialized interneurons...
nociceptor
Nociceptor
A nociceptor is a sensory receptor that responds to potentially damaging stimuli by sending nerve signals to the spinal cord and brain. This process, called nociception, usually causes the perception of pain.-History:...
s, pain sensing neurons, where they act as transducers of thermal and chemical stimuli. Hence antagonists or blockers of these channels may find application for the prevention and treatment of pain. A number of TRPV1 selective blockers are currently in clinical trial
Clinical trial
Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...
s for the treatment of various types of pain.