TRP channels

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TRP channels
Identifier
Gene name (s) TRPC, TRPV, TRPM, TRPN, TRPA, TRPP, TRPML
Transporter classification
TCDB 1.A.4
designation TRP calcium channel family
Occurrence
Parent taxon Eukaryotes

The TRP channels (English transient receptor potential channels ) are an extensive family of cellular ion channels that can be divided into seven subfamilies. The homology (DNA or amino acid sequence relationship) between the subfamilies is only moderately pronounced. All members have in common that they have 6 transmembrane regions and are permeable to cations .

A distinction is made between the following subfamilies:

  1. classic subfamily (TRPC)
  2. Vanilloid Receptor Subfamily (TRPV)
  3. Melastatin subfamily (TRPM)
  4. NOMPC subfamily (TRPN)
  5. ANKTM1 subfamily (TRPA)
  6. Mucolipin Subfamily (TRPML)
  7. Polycystine Subfamily (TRPP)

It is believed that four protein subunits in the cell membrane form an ion channel with a central pore ( tetramer ). Both homotetramers (four identical subunits) and heterotetramers (tetramers from several different subunits) are possible.

TRP channels are very old in evolutionary terms (they are already found in yeast cells, for example). The function of most of the TRP channels is still largely unclear.

Insects, for example, need TRP channels for vision and pain perception.

In humans, TRP channels play an important role in the perception of taste ( sweet , bitter , umami ), pheromones , temperature (warm, hot, cold), pain and the like. a.

The name transient receptor potential is basically the description of a phenotype of a mutant of the fruit fly Drosophila melanogaster . In the 1960s, a mutant line of Drosophila ( trp343 ) was found whose photoreceptors respond to light stimuli or depolarization only with a transient, i.e. H. rapidly inactivating membrane current reacted. In the wild type, on the other hand, the current continued as long as light hit the photoreceptor or the depolarization was maintained. After a long search for the responsible protein, TRP was finally cloned in 1989 .

The transient current in the Drosophila TRP mutants is mediated by the TRPL (for TRP-like ) channel .

TRPC channels

The letter "C" in the name of this subfamily stands for "classical" or "canonical". This designation has to do with the fact that the TRPC channels were described earlier than other TRP channels and that they are most similar to the TRP channels involved in photoreception in Drosophila .

TRPC channels are receptor- activated cation channels that can conduct various mono- and divalent cations (sodium ions, calcium ions, potassium ions) and are therefore referred to as non-selective cation channels. They are activated by the binding of ligands to metabotropic receptors that are coupled to phospholipase C. The phospholipase C produces, among other inositol trisphosphate (IP 3 ), which on its specific receptors Calcium - ions from the endoplasmic reticulum releases. Since TRPC channels have calcium conductivity , it is assumed that TRPC channels are involved in replenishing intracellular calcium stores after they have been emptied. However, it is controversial whether they are also directly memory -activated (" store-operated "), i. H. whether the emptying of the stores leads to their opening without activating a receptor.

The TRPC channels include seven representatives: TRPC1 to TRPC7, which are divided into three subfamilies. They have an amino acid identity of approx. 60–80% within the subfamilies and between 25–40% between the subfamilies.

The TRPC channels are tetrameric , i. H. four subunits form a functional channel. These can be four identical (homotetramer) or four different subunits (heterotetramer). It can be regarded as certain that heterotetramer formation is possible within the respective subfamilies, i. H. TRPC1, 4 and 5 associate with each other, as do TRPC3, 6 and 7. It was recently found that TRPC4 and 5 also associate with TRPC3 as long as TRPC1 is present. The question of the composition of the naturally occurring TRPC channels is not easy to answer, since the subunits could behave differently in heterologous expression systems than in native cells. Furthermore, there are hardly any really specific antibodies . Therefore, the data are currently still partly contradicting.

According to the phylogenetic relationship and the activation mechanism, TRPC channels are divided into three subfamilies:

TRPC1, 4 and 5

TRPC1 has been described as an independent channel or as a subunit of a heteromeric TRPC1 / TRPC4 or TRPC1 / TRPC5. TRPC1 shows a broad expression pattern in various organs and tissues. Like TRPC1, TRPC4 exists in several splice variants and is particularly strongly expressed in smooth muscle tissue. TRPC5, the closest relative of TRPC4, is particularly strongly expressed in the central nervous system. TRPC4, TRPC5 or heteromers from TRPC1 / TRPC4 or TRPC1 / TRPC5 can be activated by phospholipase C-mediated receptors via mechanisms that have not yet been molecularly understood.

TRPC2

In humans, TRPC2 is just a pseudogene ; H. the corresponding DNA sequence is available, but there is no expression of a functional TRPC2 protein. In rats and mice , TRPC2 occurs exclusively in the testes and in the vomeronasal organ . In male mice in which the TRPC2 gene was destroyed (“knock-out”), the aggressive behavior induced by pheromones is absent.

TRPC3, 6 and 7

This subgroup of TRPC channels is also referred to as DAG-sensitive TRPC channels. Their common natural agonist in heterologous expression systems is diacylglycerol , another product of phospholipase C .

TRPC3 is the calcium channel activated by erythropoietin in the membrane of erythroid cells . The molecular structure of TRPC3 has a resolution of 15 Angstroms . The large intracellular domain has a nested structure: a lattice-like outer shell functions as a sensor for agonists and modulators, while a spherical inner chamber can influence the flow of ions through the channel because it lies on a common axis with the tightly packed transmembrane domain that defines the channel pore forms. This structure shows that the TRP channels have evolved as sensors for very different signals and not as simple ion-conducting pores .

Mutations in TRPC6 lead to kidney disease, a form of familial focal sclerosing glomerulonephritis . In the third and fourth decades of life, a nephrotic syndrome occurs , which manifests itself in high protein losses in the urine. The disease leads to dependence on dialysis treatment within ten years . The protein affected by the mutation promotes the influx of calcium into the epithelial cells of the kidney corpuscles (podocytes) , which form the cell layer responsible for the blood-urinary barrier. This makes TRPC6 an important part of the slit membrane of the kidney corpuscle. In acquired diseases of the renal corpuscle , in particular membranous glomerulonephritis , the expression of TRPC6 in the epithelial cells (podocytes) is also upregulated. This leads to a reorganization of the actin cytoskeleton , a change in the calcium balance and finally to increased permeability of the glomerular filtration membrane with the transfer of protein into the urine (proteinuria) .

TRPV channels

The best-known representative of the TRPV channels is TRPV1 , which is also known as vanilloid receptor 1 (VR1). It is particularly strongly expressed in free nerve endings that act as pain receptors ( nociceptors ). It has an intracellular binding point for the hot ingredients of pepper ( piperine ) and paprika and chilli ( capsaicin ). On the other hand, it is also activated by increased temperature as well as by endogenous cannabinoids. This explains the similar quality of the sensations for “hot” or “spicy”.

TRPV1 is not only located in the plasma membrane , but also in the membrane of the endoplasmic reticulum . Like all nonspecific cation channels is TRPV1 permeable to Na + -, K + - and Ca 2+ - ions . In addition, it has a conductivity for protons .

TRPV2, which is also found in nociceptors, reacts to large heat stimuli above 50 ° C

TRPV4 is as mechano - and osmosensitiver channel in the development of hyperalgesia in inflammation involved and nerve lesions.

In the kidneys , TRPV5 is responsible for reabsorption of calcium from the primary urine. TRPV5 is expressed in the pars convoluta of the renal tubules on the apical membrane of the epithelial cells. Expression is primarily regulated by parathyroid hormone and calcitriol . Removal of the parathyroid glands ( parathyroidectomy ) reduces the expression of TRPV5, the administration of parathyroid hormone promotes the expression of TRPV5. The promoter region of the TRPV5 gene is likely controlled by 1,25-dihydroxycholecalciferol. 1,25-dihydroxycholecalciferol also promotes the expression of TRPV5 in the kidney. The increased expression of TRPV5 leads to an increased reabsorption of calcium from the primary urine and thus causes the calcium level in the blood to rise. The gene product of the Klotho gene stabilizes TRPV5 and also promotes calcium reabsorption from the primary urine.

TRPV6 is responsible for the absorption of calcium in the intestine .

TRPM channels

A mutation of TRPM1 is very likely to cause the congenital night blindness (exact name: congenital stationary night blindness (CSNB)) and the colors of the tiger piebald complex in horses.

A mutation of TRPM6 leads to a defect in magnesium uptake via the intestine and magnesium reabsorption by the kidneys. Thiazide diuretics inhibit TRPM6 expression. This leads to a loss of magnesium through the kidneys and a drop in the levels of magnesium in the blood ( hypomagnesaemia ). In a mouse model of Gitelman's syndrome , in which changes are observed similar to those observed with chronic use of thiazides, TRPM6 expression is also reduced. Chronic acidosis (acidosis) also leads to a reduction in TRPM6 expression and a magnesium deficiency, whereas an excessively high pH value in the body (alkalosis) has the opposite effects. A deficiency of magnesium in the diet leads to increased TRPM6 expression, whereas an excess of magnesium inhibits TRPM6 expression.

Activation of TRPM8 , for example by menthol , triggers a sensation of cold. Research is being carried out into selective ligands for this receptor as pain relievers.

TRPA channels

TRPA channels play a role in pain and temperature reception.

TRPA1 is the only member of this TRP family identified to date. TRPA1 is activated by a wide range of potentially harmful substances and acts as a central chemical nociceptor . In addition, TRPA1 is also activated mechanically or osmotically . There are also substances that block TRPA channels, e.g. B. probably the drug metamizole.

Classification according to the HUGO Gen Nomenclature Committee

Individual evidence

  1. ^ C Montell: The TRP superfamily of cation channels . In: Sci. STKE . 2005, No. 272, February 2005, p. Re3. doi : 10.1126 / stke.2722005re3 . PMID 15728426 .
  2. ^ Q. Tong, I. Hirschler-Laszkiewicz, W. Zhang, K. Conrad, DW Neagley, DL Barber, JY Cheung, BA Miller: TRPC3 Is the Erythropoietin-Regulated Calcium Channel in Human Erythroid Cells. In: Journal of Biological Chemistry. 283, 2008, p. 10385, doi: 10.1074 / jbc.M710231200 .
  3. ↑ Kazuhiro Mio, Toshihiko Ogura, Shigeki Kiyonaka, Yoko Hiroaki, Yukihiro Tanimura, Yoshinori Fujiyoshi, Yasuo Mori, Chikara Sato: The TRPC3 Channel Has a Large Internal Chamber Surrounded by Signal Sensing Antennas. In: Journal of Molecular Biology. 367, 2007, p. 373, doi: 10.1016 / j.jmb.2006.12.043 .
  4. ↑ MP Winn et al .: Unexpected role of TRPC6 channel in familial nephrotic syndrome: does it have clinical implications? In: J Am Soc Nephrol . Volume 17, 2006, pp. 378-387. PMID 16396961
  5. ↑ K. Tryggvason et al .: Hereditary proteinuria syndromes and mechanisms of proteinuria. In: N Engl J Med . Volume 354, 2006, pp. 1387-1401. PMID 16571882
  6. ↑ CC Möller et al .: Induction of TRPC6 Channel in Acquired Forms of Proteinuric Kidney Disease . In: J Am Soc Nephrol . No. 18 , 2007, p. 29-36 ( jasn.asnjournals.org abstract ).
  7. ↑ T Hagenacker, D Ledwig, D Büsselberg: Feedback mechanisms in the regulation of intracellular calcium ([Ca2 +] i) in the peripheral nociceptive system: role of TRPV-1 and pain related receptors . In: Cell Calcium . 43, No. 3, March 2008, pp. 215-27. doi : 10.1016 / j.ceca.2007.05.019 . PMID 17673288 .
  8. ↑ H Alessandri-Haber, OA Dina, EK Joseph, DB Reichling, JD Levine: Interaction of transient receptor potential vanilloid 4, integrin, and SRC tyrosine kinase in mechanical hyperalgesia . In: J. Neurosci. . 28, No. 5, January 2008, pp. 1046-57. doi : 10.1523 / JNEUROSCI.4497-07.2008 . PMID 18234883 .
  9. ↑ D. Gkika et al .: Critical role of the epithelial Ca2 + channel TRPV5 in active Ca2 + reabsorption as revealed by TRPV5 / calbindin-D28K knockout mice. In: J. Am. Soc. Nephrol. Volume 17, 2006, pp. 3020-3027. PMID 17005931
  10. ↑ TB Drüeke, D Prié: Klotho spins the thread of life - what does Klotho do to the receptors of fibroblast growth factor-23 (FGF23)? In: Nephrol Dial Transplant . No. 22 (6) , 2007, pp. 1524-1526 ( ndt.oxfordjournals.org ).
  11. ^ RR Bellone, SA Brooks, L Sandmeyer, BA Murphy, G Forsyth, S Archer, E Bailey, B. Grahn: Differential gene expression of TRPM1, the potential cause of congenital stationary night blindness and coat spotting patterns (LP) in the Appaloosa horse (Equus caballus). In: Genetics , 2008 Aug, 179 (4), pp. 1861-1870. Epub 2008 Jul 27. PMID 18660533
  12. ↑ LJ Macpherson, B Xiao, KY Kwan et al .: An ion channel essential for sensing chemical damage . In: J. Neurosci. . 27, No. 42, October 2007, pp. 11412-5. doi : 10.1523 / JNEUROSCI.3600-07.2007 . PMID 17942735 .
  13. ↑ XF Zhang, J Chen, CR Faltynek, RB Moreland, TR Neelands: Transient receptor potential A1 mediates an osmotically activated ion channel . In: Eur. J. Neurosci. . 27, No. 3, February 2008, pp. 605-11. doi : 10.1111 / j.1460-9568.2008.06030.x . PMID 18279313 .
  14. ↑ R. Nassini, C. Fusi, S. Materazzi, E. Coppi, T. Tuccinardi, IM Marone, F. De Logu, D. Preti, R. Tonello, A. Chiarugi, R. Patacchini, P. Geppetti, S Benemei: The TRPA1 channel mediates the analgesic action of dipyrone and pyrazolone derivatives . In: British journal of pharmacology . Volume 172, number 13, July 2015, pp. 3397-3411, doi : 10.1111 / bph.13129 , PMID 25765567 , PMC 4500374 (free full text).