TRP-channels

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.

A large family of cellular ion channels is summarized under the term "TRP channels" = transient receptor potential 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.

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, warmth, heat, cold, pressure or light impulses. For example, it is assumed that some TRP channels in the body behave like microscopic thermosensors. Some TRP channels are activated by molecules contained in everyday spices such as garlic(allicin), chili pepper (capsaicin) and 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.

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-operated, calcium-permeable, non-selective cation channels. Structurally, members of this family share 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 3D representations of the channel structures.

• TRPC1
• TRPC2
• TRPC3
• TRPC4
• TRPC5
• TRPC6
• TRPC7

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

• TRPV1
• TRPV2
• TRPV3
• TRPV4
• TRPV5
• TRPV6

TRPM channels("M" for melastatin): Members of the TRPM subfamily (e.g. TRPM8) are activated by thermal stimuli such as cold and cold-inducing substances, play a role in taste receptor cells (TRPM5) or light receptors in the retina (TRPM1) or 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 permeability for Ca2+ and Mg2+, whereby three members of the TRPM family are chanzymes that contain C-terminal enzyme domains. The role of TRPMs has been demonstrated in various tumor varieties such as prostate cancer (TRPM8 and TRPM2), breast cancer (TRPM2 and TRPM7) pancreatic cancer (TRPM2/4/7/8), melanoma (TRPM1/ TRPM8). The family of TRPM channels could therefore represent an attractive target for tumor therapy (Hantute-Ghesquier A et al. 2018).

• TRPM1
• TRPM2
• TRPM3
• TRPM4
• TRPM5
• TRPM6
• TRPM7
• TRPM8

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

TRPA1 (A1 for ankyrin)

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)

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