TRPV

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Transient receptor potential (TRP) ion channel
Trpv1 pip2 bilayer cropped.png
Homology model of the TRPV1 ion channel tetramer (where the monomers are individually colored cyan, green, blue, and magenta respective) imbedded in a cartoon representation of a lipid bilayer. PIP2 signaling ligands are represented by space-filling models (carbon = white, oxygen = red, phosphorus = orange). [1]
Identifiers
SymbolTRP
Pfam PF06011
InterPro IPR010308
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary

TRPV is a family of transient receptor potential cation channels (TRP channels) in animals. All TRPVs are highly calcium selective.

Contents

TRP channels are a large group of ion channels consisting of six protein families, located mostly on the plasma membrane of numerous human and animal cell types, and in some fungi. [2] TRP channels were initially discovered in the trp mutant strain of the fruit fly Drosophila [3] that displayed transient elevation of potential in response to light stimuli, and were therefore named "transient receptor potential" channels. [4] The name now refers only to a family of proteins with similar structure and function, not to the mechanism of their activation. Later, TRP channels were found in vertebrates where they are ubiquitously expressed in many cell types and tissues. There are about 28 TRP channels that share some structural similarity to each other. [5] These are grouped into two broad groups: group 1 includes TRPC ( "C" for canonical), TRPV ("V" for vanilloid), TRPM ("M" for melastatin), TRPN and TRPA. In group 2 there are TRPP ("P" for polycystic) and TRPML ("ML" for mucolipin).

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. [6] [7]

The TRPV channel monomeric subunit components each contain six transmembrane (TM) domains (designated S1–S6) with a pore domain between the fifth (S5) and sixth (S6) segments. [8] TRPV subunits contain three to five N-terminal ankyrin repeats. [9]

Function

TRPV proteins respond to the taste of garlic (allicin). TRPV1 contributes to heat and inflammation sensations and mediates the pungent odor and pain sensations associated with capsaicin and piperine.

Family members

The table below summarizes the functions and properties of the individual TRPV channel family members: [10] [11]

groupchannelfunctiontissue distributionCa2+/Na+
selectivity		heteromeric associated subunitsother associated proteins
1 TRPV1 vanilloid (capsaicin) receptor and noxious thermosensor (43 °C) CNS and PNS 9:1TRPV2, TRPV3 calmodulin, PI3 kinase
TRPV2 osmo- and noxious heat thermosensor (52 °C)CNS, spleen and lung3:1TRPV1
TRPV3 warmth sensor channel (33-39 °C)Skin, CNS and PNS12:1TRPV1
TRPV4 osmo- and warmth sensor channel (27-34 °C)CNS and internal organs;

human sperm [12]

6:1 aquaporin 5, calmodulin, pacsin 3
2 TRPV5 calcium-selective TRP channelintestine, kidney, placenta100:1TRPV6 annexin II / S100A10, calmodulin
TRPV6 calcium-selective TRP channelkidney, intestine130:1TRPV5annexin II / S100A10, calmodulin

Clinical significance

Mutations in TRPs have been linked to neurodegenerative disorders, skeletal dysplasia, kidney disorders, [2] and may play an important role in cancer. TRPs may make important therapeutic targets. There is significant clinical significance to TRPV1, TRPV2, and TRPV3's role as thermoreceptors, and TRPV4'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. [13] For instance, the use of TRPV1 agonists would potentially inhibit nociception at TRPV1, particularly in pancreatic tissue where TRPV1 is highly expressed. [14] The TRPV1 agonist capsaicin, found in chili peppers, has been indicated to relieve neuropathic pain. [2] TRPV1 antagonists inhibit nociception at TRPV1.

Role in cancer

Altered expression of TRP proteins often leads to tumorigenesis, clearly seen in TRPM1. [14] Particularly high levels of TRPV6 in prostate cancer have been noted. Such observations could be helpful in following cancer progression and could lead to the development of drugs over activating ion channels, leading to apoptosis and necrosis. Much research remains to be done as to whether TRP channel mutations lead to cancer progression or whether they are associated mutations.

As drug targets

Four TRPVs (TRPV1, TRPV2, TRPV3, and TRPV4) are expressed in afferent nociceptors, pain sensing neurons, where they act as transducers of thermal and chemical stimuli. Agonists, antagonists, or modulators of these channels may find application for the prevention and treatment of pain. [15] A number of TRPV1 selective blockers such as resiniferatoxin are currently in clinical trials for the treatment of various types of pain. [16]

See also

Related Research Articles

Transient receptor potential channels are a group of ion channels located mostly on the plasma membrane of numerous animal cell types. Most of these are grouped into two broad groups: Group 1 includes TRPC, TRPV, TRPVL, TRPM, TRPS, TRPN, and TRPA. Group 2 consists of TRPP and TRPML. 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), chili pepper (capsaicin), wasabi ; others are activated by menthol, camphor, peppermint, and cooling agents; yet others are activated by molecules found in cannabis or stevia. 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.

<span class="mw-page-title-main">TRPV6</span> Protein-coding gene in the species Homo sapiens

TRPV6 is a membrane calcium (Ca2+) channel protein which is particularly involved in the first step in Ca2+absorption in the intestine.

<span class="mw-page-title-main">TRPV1</span> Human protein for regulating body temperature

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 the transient receptor potential vanilloid receptor proteins that in turn are a sub-family of the transient receptor potential protein group. This protein is a member of the TRPV group of transient receptor potential family of ion channels. And a receptor being clearly present in bacteria, the oldest organisms on Earth known to express phosphatidylethanolamine, the precursor to endocannabinoids, in their cytoplasmic membranes, and fatty acid metabolites with affinity for this CB receptor are produced by cyanobacteria, which diverged from eukaryotes at least 2000 million years ago (MYA).

TRPM is a family of transient receptor potential ion channels (M standing for wikt:melastatin). Functional TRPM channels are believed to form tetramers. The TRPM family consists of eight different channels, TRPM1–TRPM8.

<span class="mw-page-title-main">TRPC1</span> Protein and coding gene in humans

Transient receptor potential canonical 1 (TRPC1) is a protein that in humans is encoded by the TRPC1 gene.

<span class="mw-page-title-main">TRPA1</span> Protein and coding gene in humans

Transient receptor potential cation channel, subfamily A, member 1, also known as transient receptor potential ankyrin 1, TRPA1, or The Wasabi Receptor, is a protein that in humans is encoded by the TRPA1 gene.

<span class="mw-page-title-main">TRPV2</span> Protein-coding gene in the species Homo sapiens

Transient receptor potential cation channel subfamily V member 2 is a protein that in humans is encoded by the TRPV2 gene. TRPV2 is a nonspecific cation channel that is a part of the TRP channel family. This channel allows the cell to communicate with its extracellular environment through the transfer of ions, and responds to noxious temperatures greater than 52 °C. It has a structure similar to that of potassium channels, and has similar functions throughout multiple species; recent research has also shown multiple interactions in the human body.

<span class="mw-page-title-main">TRPV4</span> Protein-coding gene in the species Homo sapiens

Transient receptor potential cation channel subfamily V member 4 is an ion channel protein that in humans is encoded by the TRPV4 gene.

<span class="mw-page-title-main">TRPM8</span> Protein-coding gene in the species Homo sapiens

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 transducer of cold somatosensation in humans. In addition, mints can desensitize a region through the activation of TRPM8 receptors.

<span class="mw-page-title-main">TRPM3</span> Protein-coding gene in the species Homo sapiens

Transient receptor potential cation channel subfamily M member 3 is a protein that in humans is encoded by the TRPM3 gene.

<span class="mw-page-title-main">TRPV3</span> Protein-coding gene in the species Homo sapiens

Transient receptor potential cation channel, subfamily V, member 3, also known as TRPV3, is a human gene encoding the protein of the same name.

<span class="mw-page-title-main">TRPV5</span> Protein-coding gene in the species Homo sapiens

Transient receptor potential cation channel subfamily V member 5 is a calcium channel protein that in humans is encoded by the TRPV5 gene.

<span class="mw-page-title-main">Iodoresiniferatoxin</span> Chemical compound

Iodoresiniferatoxin (I-RTX) is a strong competitive antagonist of the Transient Receptor Potential Vanilloid 1 (TRPV1) receptor. I-RTX is derived from resiniferatoxin (RTX).

Relief from chronic pain remains a recognized unmet medical need. Consequently, the search for new analgesic agents is being intensively studied by the pharmaceutical industry. The TRPV1 receptor is a ligand gated ion channel that has been implicated in mediation of many types of pain and therefore studied most extensively. The first competitive antagonist, capsazepine, was first described in 1990; since then, several TRPV1 antagonists have entered clinical trials as analgesic agents. Should these new chemical entities relieve symptoms of chronic pain, then this class of compounds may offer one of the first novel mechanisms for the treatment of pain in many years.

Zucapsaicin (Civanex) is a medication used to treat osteoarthritis of the knee and other neuropathic pain. It is applied three times daily for a maximum of three months. Zucapsaicin is a member of phenols and a member of methoxybenzenes It is a modulator of transient receptor potential cation channel subfamily V member 1 (TRPV-1), also known as the vanilloid or capsaicin receptor 1 that reduces pain, and improves articular functions. It is the cis-isomer of capsaicin. Civamide, manufactured by Winston Pharmaceuticals, is produced in formulations for oral, nasal, and topical use.

<span class="mw-page-title-main">Vanillotoxin</span> Chemical compound

Vanillotoxins are neurotoxins found in the venom of the tarantula Psalmopoeus cambridgei. They act as agonists for the transient receptor potential cation channel subfamily V member 1 (TRPV1), activating the pain sensory system. VaTx1 and 2 also act as antagonists for the Kv2-type voltage-gated potassium channel (Kv2), inducing paralytic behavior in small animals.

<span class="mw-page-title-main">Vanilloids</span> Chemical compounds containing a vanillyl group

The vanilloids are compounds which possess a vanillyl group. They include vanillyl alcohol, vanillin, vanillic acid, acetovanillon, vanillylmandelic acid, homovanillic acid, capsaicin, etc. Isomers are the isovanilloids.

The transient receptor potential Ca2+ channel (TRP-CC) family (TC# 1.A.4) is a member of the voltage-gated ion channel (VIC) superfamily and consists of cation channels conserved from worms to humans. The TRP-CC family also consists of seven subfamilies (TRPC, TRPV, TRPM, TRPN, TRPA, TRPP, and TRPML) based on their amino acid sequence homology:

  1. the canonical or classic TRPs,
  2. the vanilloid receptor TRPs,
  3. the melastatin or long TRPs,
  4. ankyrin (whose only member is the transmembrane protein 1 [TRPA1])
  5. TRPN after the nonmechanoreceptor potential C (nonpC), and the more distant cousins,
  6. the polycystins
  7. and mucolipins.
<span class="mw-page-title-main">HC-067047</span> Chemical compound

HC-067047 is a drug which acts as a potent and selective antagonist for the TRPV4 receptor. It has been used to investigate the role of TRPV4 receptors in a number of areas, such as regulation of blood pressure, bladder function and some forms of pain, as well as neurological functions.

<span class="mw-page-title-main">AMG-517</span> Chemical compound

AMG-517 is a drug which acts as a potent and selective blocker of the TRPV1 ion channel. It was developed as a potential treatment for chronic pain, but while it was an effective analgesic in animal studies it was dropped from human clinical trials at Phase I due to producing hyperthermia as a side effect, as well as poor water solubility. It is still used in scientific research into the function of the TRPV1 channel and its role in pain and inflammation, and has been used as a template for the design of several newer analogues which have improved properties.

References

  1. ↑ Brauchi S, Orta G, Mascayano C, Salazar M, Raddatz N, Urbina H, Rosenmann E, Gonzalez-Nilo F, Latorre R (June 2007). "Dissection of the components for PIP2 activation and thermosensation in TRP channels". Proceedings of the National Academy of Sciences of the United States of America. 104 (24): 10246–51. Bibcode:2007PNAS..10410246B. doi: 10.1073/pnas.0703420104 . PMC   1891241 . PMID   17548815.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  2. 1 2 3 Winston KR, Lutz W (March 1988). "Linear accelerator as a neurosurgical tool for stereotactic radiosurgery". Neurosurgery. 22 (3): 454–64. doi:10.1097/00006123-198803000-00002. PMID   3129667.
  3. ↑ Cosens DJ, Manning A (October 1969). "Abnormal electroretinogram from a Drosophila mutant". Nature. 224 (5216): 285–7. Bibcode:1969Natur.224..285C. doi:10.1038/224285a0. PMID   5344615. S2CID   4200329.
  4. ↑ Montell C, Rubin GM (April 1989). "Molecular characterization of the Drosophila trp locus: a putative integral membrane protein required for phototransduction". Neuron. 2 (4): 1313–23. doi:10.1016/0896-6273(89)90069-x. PMID   2516726. S2CID   8908180.
  5. ↑ Islam MS, ed. (January 2011). Transient Receptor Potential Channels. Advances in Experimental Medicine and Biology. Vol. 704. Berlin: Springer. p. 700. ISBN   978-94-007-0264-6.
  6. ↑ Vennekens R, Owsianik G, Nilius B (2008). "Vanilloid transient receptor potential cation channels: an overview". Current Pharmaceutical Design. 14 (1): 18–31. doi:10.2174/138161208783330763. PMID   18220815.
  7. ↑ Cheng W, Yang F, Takanishi CL, Zheng J (March 2007). "Thermosensitive TRPV channel subunits coassemble into heteromeric channels with intermediate conductance and gating properties". J. Gen. Physiol. 129 (3): 191–207. doi:10.1085/jgp.200709731. PMC   2151614 . PMID   17325193.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  8. ↑ Vannier B, Zhu X, Brown D, Birnbaumer L (April 1998). "The membrane topology of human transient receptor potential 3 as inferred from glycosylation-scanning mutagenesis and epitope immunocytochemistry". J. Biol. Chem. 273 (15): 8675–9. doi:10.1074/jbc.273.15.8675. PMID   9535843.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  9. ↑ Montell C (February 2005). "The TRP superfamily of cation channels". Sci. STKE. 2005 (272): re3. doi:10.1126/stke.2722005re3. PMID   15728426. S2CID   7326120.
  10. ↑ Clapham DE, Julius D, Montell C, Schultz G (December 2005). "International Union of Pharmacology. XLIX. Nomenclature and structure-function relationships of transient receptor potential channels". Pharmacological Reviews. 57 (4): 427–50. doi:10.1124/pr.57.4.6. PMID   16382100. S2CID   17936350.
  11. ↑ Venkatachalam K, Montell C (2007). "TRP channels". Annual Review of Biochemistry. 76 (1): 387–417. doi:10.1146/annurev.biochem.75.103004.142819. PMC   4196875 . PMID   17579562.
  12. ↑ Mundt N, Spehr M, Lishko PV (July 2018). "TRPV4 is the temperature-sensitive ion channel of human sperm". eLife. 7. doi:10.7554/elife.35853. PMC   6051745 . PMID   29963982.
  13. ↑ Levine JD, Alessandri-Haber N (August 2007). "TRP channels: targets for the relief of pain" (PDF). Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 1772 (8): 989–1003. doi:10.1016/j.bbadis.2007.01.008. PMID   17321113. S2CID   11450214.
  14. 1 2 Prevarskaya N, Zhang L, Barritt G (August 2007). "TRP channels in cancer" (PDF). Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 1772 (8): 937–46. doi:10.1016/j.bbadis.2007.05.006. PMID   17616360.
  15. ↑ Levine JD, Alessandri-Haber N (August 2007). "TRP channels: targets for the relief of pain" (PDF). Biochim. Biophys. Acta. 1772 (8): 989–1003. doi:10.1016/j.bbadis.2007.01.008. PMID   17321113. S2CID   11450214.
  16. ↑ Szallasi A, Cortright DN, Blum CA, Eid SR (May 2007). "The vanilloid receptor TRPV1: 10 years from channel cloning to antagonist proof-of-concept". Nature Reviews. Drug Discovery. 6 (5): 357–72. doi:10.1038/nrd2280. PMID   17464295. S2CID   6276214.
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