TRP-channels

Last updated on: 18.12.2020

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History
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TRP channels are phylogenetically early, highly conserved signaling pathways (they can already be detected in yeast cells). The first TRP channel was identified in 1989 in the context of visual perception in Drosophila melanogaster. In a Drosophila mutant (trp343), it was shown that its photoreceptors responded to light stimuli only with a "transient", i.e. rapidly inactivating, membrane current, independent of the duration of its exposure. In the non-mutated wild type, however, the current flow persisted as long as light acted on the photoreceptor. The mutant protein -TRP- was cloned in 1989. Thus, for historical reasons, the name "transient receptor potential" - TRP- refers to the description of a phenotype of a mutant of the fruit fly Drosophila melanogaster.

Definition
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The term "TRP channels" = transient receptor potential channels, covers a large family of cellular ion channels. To date, 28 Trp channel genes have been identified in mammals (Nilius B et al. 2011). TRP channels exert important functions in primary signaling pathways in both vertebrates and non-vertebrates by being responsible for the regulated influx of Ca2+ into a cell after activation.

Thus, in humans, TRP channels play an important receptive role in the processing of different types of taste (sweet, bitter, umami). Furthermore, in the perception and processing of pain, heat, cold, pressure or light impulses. For example, some TRP channels in the body are thought to behave like microscopic thermosensors. Some TRP channels are activated by molecules found in everyday spices such as garlic(allicin), chili pepper (capsaicin), wasabi (allyl isothiocyanate). Other channels are activated by menthol, camphor, peppermint and cannabis . Some channels act as mechano-sensors for osmotic pressure, volume, stretch and vibration.

Classification
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The subfamilies known to date are:

  • TRPN(NOMPC)
  • TRPC (C for canonical/canonical),
  • TRPM(Melastatin),
  • TRPV(Vanilloid),
  • TRPP (polycystin),
  • TRPA (ankyrin)
  • TRPML (mucolipin)
  • TRPC ("C" for canonical)

TRPC: TRPCs ("C" stands for canonical) represent a group of receptor-driven, calcium-permeable, non-selective cation channels. Structurally, members of this family possess a number of similar features, including 3 or 4 ankyrin repeats near the N-terminus and a TRP-box motif at the proximal C-terminus. Cryogenic electron microscopy was used to construct several high-resolution structures of TRPC channels with 3-D representations of the channel structures.

TRPV ("V" for vanilloid thermosensitive ion channels). A group of six thermosensitive TRP channels is known. The perception of painful heat is mediated by two heat receptors, TRP V1 and TRP V2.

TRPM channels("M" for melastatin): Members of the TRPM subfamily (e.g. TRPM8) are activated, among other things, by thermal stimuli such as cold and cold-mediating substances, continue to play a role in taste receptor cells (TRPM5) or light receptors in the retina (TRPM1), or they are significantly involved in magnesium uptake, e.g. in the kidney and intestine. Members of the TRPM family ("melastatin") fall into the subclass of TRP channels with different permeabilities for Ca2+ and Mg2+, and three members of the TRPM family are chancymes containing C-terminal enzyme domains. The role of TRPMs has been demonstrated in diverse tumor varieties such as prostate cancer (TRPM8 and TRPM2), breast cancer (TRPM2 and TRPM7) pancreatic cancer (TRPM2/4/7/8), melanoma (TRPM1/ TRPM8). Thus, the TRPM channel family may represent an attractive target for tumor therapy (Hantute-Ghesquier A et al. 2018).

TRPN channel: TRPN was given the name "no mechanoreceptor potential C (nompC)". Since its discovery in fruit flies, TRPN homologs have been discovered and characterized in worms, frogs, and zebrafish. No functions have yet been reported in vertebrates and thus in humans. TRPN appears to be responsible for functions in mechanosensory systems.

TRPA1 (A1 for ankyrin)

General information
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The homology (DNA or amino acid sequence relatedness) between the subfamilies is only moderately pronounced. The primary structure of TRP channels, however, is comparable. It features 6 transmembrane sequences with a pore loop and a cytoplasmically localized C- and N-terminus each. However, this primary structure is not specific to TRP channels but rather mirrors the architecture of known ion channels (e.g., voltage-gated potassium, sodium, and calcium channels). Another common feature is a TRP motif 25 amino acids in length. Within the cytoplasmic N-terminus of TRPA, TRPC and TRPV channels lie ankyrin repeat sequences, whereas TRPC and TRPM channels have proline-rich regions.

Functional properties of TRP channels: The vast majority of TRP channels are permeable to monovalent cations and to Ca2+ and Mg2+. Exceptions are TRPM4 and TRPM5, which are exclusively selective for monovalent cations. TRPV5 and TRPV6 are exclusively permeable for Ca2+. TRP channels show no voltage dependence unlike the voltage-dependent calcium or sodium channels. They depolarize cells from the resting potential (usually -70 mV in mammalian cells) to 0 mV.

Mutations in genes encoding TRP channels are the cause of several inherited human diseases (so-called"TRP channelopathies") affecting the cardiovascular, renal, skeletal, nervous, and skin systems (Kaneko Y et al. 2014; Nilius B et al. 2011).

TRP channels are also promising targets for drug development. For example, a number of potent small molecule TRPV channel antagonists (occasionally TRPM antagonists) are now showing therapeutic benefit in the treatment of inflammatory and neuropathic pain as well as cardiometabolic diseases (Ma J et al. 2017, Moran MM et al. 2018)

Literature
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  1. Andersen HH et al. (2015) Human surrogate models of histaminergic and non-histaminergic itch". Acta Dermato-Venereologica. 95: 771-777.
  2. Basso L et al (2017) Transient receptor potential channels in neuropathic pain. Curr Opin Pharmacol 32:9-15.
  3. Brożyna AA et al. (2017) TRPM1 (melastatin) expression is an independent predictor of overall survival in clinical AJCC stage I and II melanoma patients. J Cutan Pathol 44: 328-337.
  4. Cuffe JS et al. (2015) Differential mRNA expression and glucocorticoid-mediated regulation of TRPM6 and TRPM7 in the heart and kidney throughout murine pregnancy and development. PLoS One:e0117978.
  5. Dietrich A (2019) Transient receptor potential (TRP) channels in health and disease. Cells 8:413.
  6. Dutta B et al. (2019) Role of macrophage TRPV4 in inflammation. Lab Invest 100:178-185.
  7. Hantute-Ghesquier A et al (2018) TRPM Family Channels in Cancer. Pharmaceuticals (Basel) 11:58.
  8. Hirschler-Laszkiewicz I et al. (2018) The human ion channel TRPM2 modulates neuroblastoma cell survival and mitochondrial function through Pyk2, CREB, and MCU activation. Am J Physiol Cell Physiol 315:C571-C586.
  9. Khalil M et al (2018) Functional Role of Transient Receptor Potential Channels in Immune Cells and Epithelia. Front Immunol 9:174.
  10. Kaneko Y et al (2014) Transient receptor potential (TRP) channels: a clinical perspective. Br J Pharmacol 171:2474-507.
  11. Luongo F et al. (2018) TRPM6 is essential for Magnesium Uptake and Epithelial Cell Function in the Colon. Nutrients 18:784.
  12. Ma J et al (2017) Targeting Transient Receptor Potential Channels in Cardiometabolic Diseases and Myocardial Ischemia Reperfusion Injury. Curr Drug Targets. 18:1733-1745.
  13. Mathar I et al (2014) Handb Exp Pharmacol 222:461-487.
  14. Moran MM et al. (2018) Targeting nociceptive transient receptor potential channels to treat chronic pain: current state of the field. Br J Pharmacol 175:2185-2203.
  15. Nilius B et al (2011) The transient receptor potential family of ion channels. Genome Biol 12:218.
  16. Wang Y et al. (2017) Targeting transient receptor potential canonical channels for Diseases of the Nervous System. Curr Drug Targets.18:1460-1465.
  17. Vennekens R et al (2018) TRPM5 in the battle against diabetes and obesity. Acta Physiol (Oxf) doi: 10.1111/apha.12949.
  18. Vriens J et al (2011) TRPM3 is a nociceptor channel involved in the detection of noxious heat. Neuron 70: 482-494
  19. Vriens J et al (2018) Sensing the heat with TRPM3. Pflugers Arch 470:799-807.
  20. Zhan L et al (2017) The role of TRPV4 in fibrosis. Gene 642:1-8.

Incoming links (3)

Capsici fructus acer; Pain; Sharps;

Last updated on: 18.12.2020