Transient receptor potential channel

The TRP channels (English transient receptor potential channels) are a large family of cellular ion channels, which can be divided into seven subfamilies. The homology ( DNA or amino acid sequence relationship ) between the subfamilies is only moderate. Common to all members that they have six transmembrane regions and are permeable to cations.

We distinguish the following subfamilies:

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

TRP channels are evolutionarily very old ( they can be found, for example, already in yeast cells ). However, the function of most TRP channels is still largely unclear.

Insects, for example, need to see and TRP channels in pain perception.

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

The name " transient receptor potential " is basically a description of a phenotype of a mutant of the fruit fly Drosophila melanogaster. In the 1960s, they found a mutated line of Drosophila ( trp343 ) whose photoreceptors respond to light stimuli or depolarization with a transient, that is rapidly inactivating membrane current. In the wild type, however, the flow stopped, while the light struck on 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 TRP mutants of Drosophila is mediated by the channel TRPL ( TRP -like).

TRPC channels

The letter " C " in the name of this subfamily represents " classical " or " canonical". This name has to do with the fact that the TRPC channels have been described rather than other TRP channels and that they have the most similarity to the TRP channels involved in the photoreception in Drosophila.

TRPC channels are receptor- activated cation channels, the various mono-and divalent cations (sodium ions, calcium ions, potassium ions ) to guide and are thus referred to as non-selective cation channels. They are activated by binding of ligands to metabotropic receptors that are coupled to the phospholipase C. The phospholipase C produces, among other inositol trisphosphate (IP3 ), which releases calcium ions via its specific receptors from the endoplasmic reticulum. Because TRPC channels have a calcium conductance, it is presumed that TRPC channels in the refilling of intracellular calcium stores are involved they are empty. However, it is debatable whether they store also activated directly ( "store -operated " ) are, that is, whether the depletion of memory even without activation of a receptor leads to its opening.

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

The TRPC channels are structured tetramer, ie four subunits form a functional channel. It may be four identical ( homotetramer ) or four different subunits ( heterotetramer ) act. It can be regarded as certain that within the respective sub- families Heterotetramerbildung is possible, i.e., TRPC1, 4 and 5, associate with each other, just as TRPC3, 6 and 7, has recently been found that even with 5 TRPC4 or TRPC3 associated, as long as TRPC1 is present. The question of the composition of naturally occurring TRPC channels is not easy to answer, because the subunits could behave differently in heterologous expression systems than in native cells. Furthermore, there is no real -specific antibody. Therefore, the data for these currently still partially contradictory.

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

TRPC1, 4 and 5

TRPC1 has been described as a separate channel or as a subunit of a heteromeric TRPC1/TRPC4- or TRPC1/TRPC5. TRPC1 shows a broad expression pattern in different organs and tissues. TRPC4 as well as TRPC1 exists in several splice variants and is highly expressed in smooth muscle tissue. TRPC5, the closest relative of TRPC4 is highly expressed in the central nervous system. TRPC4, TRPC5 or heteromers of TRPC1/TRPC4 or TRPC1/TRPC5 can by phospholipase C -mediated receptors on not yet understood molecular mechanisms are activated.

TRPC2

In humans TRPC2 is a pseudogene, i.e., the corresponding DNA sequence is present, but there is no expression of a functional protein TRPC2 instead. In rats and mice TRPC2 occurs exclusively in the testis and in the vomeronasal organ. In male mice, in which the TRPC2 gene was destroyed ( "knock -out"), lacking the pheromones induced aggressive behavior.

TRPC3, 6 and 7

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

TRPC3 is the erythropoietin -activated calcium channel in the membrane of erythroid cells. The molecular structure of TRPC3 is available with a resolution of 15 angstroms. The large intracellular domain has a nested structure: A grid-like outer shell functioning as a sensor for agonists and modulators, while a spherical inner chamber may affect the flow of ions through the channel, as it lies on a common axis with the densely packed transmembrane domain, the channel pore, the formed. This structure shows that the TRP channels are evolved as sensors for very different signals and not as a simple ion-conducting pore.

Mutations of TRPC6 lead to kidney disease, a form of familial focal sclerosing glomerulonephritis. In the third and fourth decade of life, it comes to the appearance of nephrotic syndrome, which manifests itself as high protein loss in the urine. The condition leads within ten years of the dependence of the dialysis treatment. The affected by the mutation protein promotes calcium influx into the epithelial cells of the renal ( podocytes ), which form the person responsible for the blood- urine barrier cell layer. Thus, TRPC6 an important part of the slit diaphragm of the renal corpuscle. In acquired disorders of the renal corpuscle, in particular the membranous glomerulonephritis, expression of TRPC6 in the epithelial cells ( podocytes ) is also up-regulated. This leads to a reorganization of the actin cytoskeleton, a change in the calcium balance and eventually to increased permeability of the glomerular filtration membrane with passage 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 ). He is particularly strongly expressed in free nerve endings that act as pain receptors ( nociceptors ). He has an intracellular binding site for the sharp components of pepper ( piperine ) and paprika or chili (capsaicin ). On the other hand, it is also activated by elevated temperature as well as by endogenous cannabinoids. Thus, the similar quality of sensations for " hot " or declared " sharp".

TRPV1 is located not only in the plasma membrane, but also in the membrane of the endoplasmic reticulum. Like all non-specific cation channels TRPV1 is permeable to Na -, K - and Ca2 ions. In addition, he has, however, a proton conductivity.

TRPV2 which also occurs in nociceptors respond to intense heat stimuli above 50 ° C.

TRPV4 is implicated as a mechano- and osmosensitiver channel in the development of hyperalgesia in inflammation and nerve injury.

In the kidney, TRPV5 is responsible for the reabsorption of calcium from the primary. TRPV5 kidney tubule is expressed on the apical membrane of epithelial cells in the pars convoluta. The expression is regulated primarily by parathyroid hormone and calcitriol. Removal of the parathyroid glands ( parathyroidectomy ) reduced the expression of TRPV5, the administration of parathyroid hormone promotes the expression of TRPV5. The promoter region of the gene is likely to be controlled TRPV5 of 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 and thus causes an increase in the calcium level in the blood. The gene product of the gene Klotho stabilized 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 reasonably likely congenital night blindness ( Exact name: congenital stationary night blindness, English: congenital stationary night blindness ( CSNB )) and the colors of the Tigerschecken complex in the horse.

Mutation of TRPM6 causes a defect in magnesium absorption from the gut and the magnesium reabsorption by the kidneys. Thiazide diuretics inhibit TRPM6 expression. This leads to a loss of magnesium by the kidney and decrease of the magnesium level in the blood ( hypomagnesaemia ). In a mouse model of Gitelman syndrome, is observed the similar changes as in case of chronic ingestion of thiazides, the TRPM6 expression is also reduced. Chronic acidosis ( acidosis) also leads to a reduction of the expression TRPM6 and magnesium deficiency, too high a pH - value of the body ( alkalosis), however, has the opposite effects. A lack of magnesium in the diet resulting in increased TRPM6 expression, whereas a magnesium excess inhibits TRPM6 expression.

TRPA channels

TRPA channels play a role in pain and temperature reception.

TRPA1 is the only previously unidentified member of the TRP family. TRPA1 is activated by a wide range of potentially harmful substances and acts as a central chemical nociceptor. In addition, TRPA1 is activated mechanically or osmotically.

Classification according to the HUGO Gene Nomenclature Committee

• TRPC ( canonical ): TRPC1, TRPC2, TRPC3, TRPC4, TRPC5, TRPC6, TRPC7
• TRPV ( vanilloid ): TRPV1, TRPV2, TRPV3, TRPV4, TRPV5, TRPV6
• TRPM ( melastatin ): TRPM1, TRPM2, TRPM3, TRPM4, TRPM5, TRPM6, TRPM7, TRPM8