TRP-каналы: Классификация, функции и регуляция.

Class of transport proteins

Transient receptor potential channels (TRP 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 ( "C" for canonical), TRPV ("V" for vanilloid), TRPVL ("VL" for vanilloid like), TRPM ("M" for melastatin), TRPS ("S" for soromelastatin), TRPN ("N" for mechanoreceptor potential C), and TRPA ("A" for ankyrin). Group 2 consists of TRPP ("P" for polycystic) and TRPML ("ML" for mucolipin). Many of these channels mediate a variety of sensations such as pain, temperature, different kinds of taste, 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 (allyl isothiocyanate); others are activated by menthol, camphor, peppermint, and cooling agents; yet others are activated by molecules found in cannabis (i. e., THC, CBD and CBN) 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. These ion channels have a relatively non selective permeability to cations, including sodium, calcium and magnesium. TRP channels were initially discovered in the so called "transient receptor potential" mutant (trp mutant) strain of the fruit fly Drosophila, hence their name (see History of Drosophila TRP channels below). Later, TRP channels were found in vertebrates where they are ubiquitously expressed in many cell types and tissues. Most TRP channels are composed of 6 membrane spanning helices with intracellular N and C termini. Mammalian TRP channels are activated and regulated by a wide variety of stimuli and are expressed throughout the body.

In the animal TRP superfamily there are currently 9 proposed families split into two groups, each family containing a number of subfamilies. Below are members of the sub families and a brief description of each:

TRP channels are composed of 6 membrane spanning helices (S1 S6) with intracellular N and C termini. Mammalian TRP channels are activated and regulated by a wide variety of stimuli including many post transcriptional mechanisms like phosphorylation, G protein receptor coupling, ligand gating, and ubiquitination. The receptors are found in almost all cell types and are largely localized in cell and organelle membranes, modulating ion entry. Most TRP channels form homo or heterotetramers when completely functional. The ion selectivity filter, pore, is formed by the complex combination of p loops in the tetrameric protein, which are situated in the extracellular domain between the S5 and S6 transmembrane segments. As with most cation channels, TRP channels have negatively charged residues within the pore to attract the positively charged ions.

Each channel in this group is structurally unique, which adds to the diversity of functions that TRP channels possess, however, there are some commonalities that distinguish this group from others. Starting from the intracellular N terminus there are varying lengths of ankryin repeats (except in TRPM) that aid with membrane anchoring and other protein interactions. Shortly following S6 on the C terminal end, there is a highly conserved TRP domain (except in TRPA) which is involved with gating modulation and channel multimerization. Other C terminal modifications such as alpha kinase domains in TRPM7 and M8 have been seen as well in this group. TRP channels were initially discovered in the trp mutant strain of the fruit fly Drosophila TRPML channels function as intracellular calcium release channels and thus serve an important role in organelle regulation. Thermo TRP channels have a C terminal domain that is responsible for thermosensation and have a specific interchangeable region that allows them to sense temperature stimuli that is tied to ligand regulatory processes. Although most TRP channels are modulated by changes in temperature, some have a crucial role in temperature sensation. There are at least 6 different Thermo TRP channels and each plays a different role. For instance, TRPM8 relates to mechanisms of sensing cold, TRPV1 and TRPM3 contribute to heat and inflammation sensations, and TRPA1 facilitates many signaling pathways like sensory transduction, nociception, inflammation and oxidative stress. TRPM5 is activated by the sweet glycosides found in the stevia plant. Several other TRP channels play a significant role in chemosensation through sensory nerve endings in the mouth that are independent from taste buds. TRPA1 responds to mustard oil (allyl isothiocyanate), wasabi, and cinnamon, TRPA1 and TRPV1 responds to garlic (allicin), TRPV1 responds to chilli pepper (capsaicin), TRPM8 is activated by menthol, camphor, peppermint, and cooling agents; TRPV2 is activated by molecules (THC, CBD and CBN) found in marijuana.

The trp mutant fruit flies, which lack a functional copy of trp gene, are characterized by a transient response to light, unlike wild type flies that demonstrate a sustained photoreceptor cell activity in response to light. A distantly related isoform of TRP channel, TRP like channel (TRPL), was later identified in Drosophila photoreceptors, where it is expressed at approximately 10 to 20 fold lower levels than TRP protein. A mutant fly, trpl, was subsequently isolated. Apart from structural differences, the TRP and TRPL channels differ in cation permeability and pharmacological properties. TRP/TRPL channels are solely responsible for depolarization of insect photoreceptor plasma membrane in response to light. When these channels open, they allow sodium and calcium to enter the cell down the concentration gradient, which depolarizes the membrane. Variations in light intensity affect the total number of open TRP/TRPL channels, and, therefore, the degree of membrane depolarization. These graded voltage responses propagate to photoreceptor synapses with second order retinal neurons and further to the brain. It is important to note that the mechanism of insect photoreception is dramatically different from that in mammals. Excitation of rhodopsin in mammalian photoreceptors leads to the hyperpolarization of the receptor membrane but not to depolarization as in the insect eye. In Drosophila and, it is presumed, other insects, a phospholipase C (PLC) mediated signaling cascade links photoexcitation of rhodopsin to the opening of the TRP/TRPL channels. Although numerous activators of these channels such as phosphatidylinositol 4,5 bisphosphate (PIP2) and polyunsaturated fatty acids (PUFAs) were known for years, a key factor mediating chemical coupling between PLC and TRP/TRPL channels remained a mystery until recently. It was found that breakdown of a lipid product of PLC cascade, diacylglycerol (DAG), by the enzyme diacylglycerol lipase, generates PUFAs that can activate TRP channels, thus initiating membrane depolarization in response to light. This mechanism of TRP channel activation may be well preserved among other cell types where these channels perform various functions.

Mutations in TRPs have been linked to neurodegenerative disorders, skeletal dysplasia, kidney disorders, For instance the use of TRPV1 agonists would potentially inhibit nociception at TRPV1, particularly in pancreatic tissue where TRPV1 is highly expressed. The TRPV1 agonist capsaicin, found in chili peppers, has been indicated to relieve neuropathic pain. TRPM family of ion channels are particularly associated with prostate cancer where TRPM2 (and its long noncoding RNA TRPM2 AS), TRPM4, and TRPM8 are overexpressed in prostate cancer associated with more aggressive outcomes. TRPM3 has been shown to promote growth and autophagy in clear cell renal cell carcinoma, TRPM4 is overexpressed in diffuse large B cell lymphoma associated with poorer survival, while TRPM5 has oncogenic properties in melanoma. TRP channels take center stage in modulating chemotherapy resistance in breast cancer. Some TRP channels such as TRPA1 and TRPC5 are tightly associated with drug resistance during cancer treatment; TRPC5 mediated high Ca2+ influx activates the transcription factor NFATC3 (Nuclear Factor of Activated T Cells, Cytoplasmic 3), which triggers p glycoprotein (p gp) transcription. The overexpression of p gp is widely recognized as a major factor in chemoresistance in cancer cells, as it functions as an active efflux pump that can remove various foreign substances, including chemotherapeutic agents, from within the cell. and Drosophila melanogaster flies. At higher concentrations, LPS activates other members of the sensory TRP channel family as well, such as TRPV1, TRPM3 and to some extent TRPM8. LPS is recognized by TRPV4 on epithelial cells. TRPV4 activation by LPS was necessary and sufficient to induce nitric oxide production with a bactericidal effect.

The original TRP mutant in Drosophila was first described by Cosens and Manning in 1969 as "a mutant strain of D. melanogaster which, though behaving phototactically positive in a T maze under low ambient light, is visually impaired and behaves as though blind". It also showed an abnormal electroretinogram response of photoreceptors to light which was transient rather than sustained as in the "wild type". The identity of the mutated protein was unknown until it was cloned by Craig Montell, a post doctoral researcher in Gerald Rubin's research group, in 1989, who noted its predicted structural relationship to channels known at the time The TRPL channel was cloned and characterized in 1992 by the research group of Leonard Kelly. In 2013, Montell and his research group found that the TRPL (TRP like) cation channel was a direct target for tastants in gustatory receptor neurons and could be reversibly down regulated.