Research Area

TRP Family


Introduction of TRP family

The transient receptor potential (TRP) channel protein family consists of a special family of cation channel proteins that are closely related to Ca2+ and play an extremely important role in sensory physiology. It has a wide range of effects, including short-term effects such as cell contraction, secretion, sensory signal transduction, and long-term effects such as cell growth, proliferation, and death. TRP is a gating molecule in the sensory system and is an intermediary between the external environment and the nervous system, which converts thermal, chemical, and mechanical stimuli into inward currents.

The family members of TRP family and their structure respectively

The mammalian TRP channel protein family includes seven proteins that each contains six transmembrane domains, which can be divided into two broad categories. The first class of TRPs includes TRPA, TRPC, TRPM, TRPN, and TRPV, and their transmembrane structures domain has sequence homology and contains a C-terminal 23-25 amino acid "TRP domain" in the 6th transmembrane domain; the second category includes TRPP and TRPML, with fewer TRPs than the first sequence homology, and an extracellular loop between the first and second transmembrane domains, with similar primary structural sequences and predicted topological structure. These TRP proteins have different permeability for different cations, lack the positively charged amino acid residues necessary for voltage-gated channels in their fourth transmembrane domain and form pores in the S5 and S6 hydrophilic regions; Both the N-terminus and the C-terminus are intracellular, and the N-terminus has an ankyrin repeat and a coiled-coil domain that binds to the protein or cytoskeleton, and this structure is required for TRP protein interaction.

Research status of TRP family and the mechanism of their physiological sensory function

Mammalian TRP studies involve a highly selective entry mechanism for non-excitatory Ca2+, particularly in relation to calcium pool regulation of Ca2+ influx. The TRP channel protein is closely related to the Ca2+ channel (store-operated channels, SOC), and SOCs is one of the main pathways for Ca2+ to enter non-excitable cells. Activation of TRP involves several factors, such as physical stimuli (such as heat, volume expansion, shear stress, osmotic pressure), chemical stimuli (such as phorbol ester), electrical stimulation, and ligand activation. In the TRPV1 signal pathway, the nerve growth factor (NGF) can make the damage more sensitive by increasing TRPV1 activity. TRPV 1 regulates the adaptation to pain stimuli through phosphorylation and dephosphorylation. PKA and PKC phosphorylation sites are present in all TRPs, and phosphorylation-related PI3K and SH2 domains are also found in several TRPs. NGF-activated receptor tyrosine kinase RTK phosphorylates the receptor's own Tyr, leading to further enzymatic activity, which in turn catalyzes the phosphorylation of Tyr on its target protein. The phospholipase PLC-γ is activated, PLC -γ amplifies the excited PLC signal, and the amplification of the excitation signal is necessary for ion pool loss and activation of the ion channel. The enzyme decomposes phosphoinositide-4,5-diphosphate (PIP2) into second messenger diglyceride (DAG) and inositol triphosphate (IP3), the former activates PKC and leads to TRPV1 phosphorylation. NGF can also activate TRPV1 via the PI3K pathway, and bradykinin (BK) can also activate PKC to phosphorylate TRPV1. TRPV4 is activated by cytochrome P450, and cytochrome P450 is a product of SOCs regulating arachidonic acid metabolism. The physiological sensory functions involved in the TRP protein family are specifically described below. Mammalian perception of temperature is dependent on TRPV and TRPM in the TRP family of proteins, which are turned on by cold or heat stimuli, activate skin sensory nerve cells and transmit external information to the spinal cord and brain. The precise expression, localization, and function of TRP are key to nociceptive effects, and the various post-translational modifications of these proteins that can be made after inflammation make pain perception more sensitive. TRPV1 can be activated by heat and H+ and can also be activated by chemicals such as capsaicin. The taste cells of the human tongue are not sensitive to the "spicy" of the pepper, which is felt by the pain fibers activated by capsaicin. In the 1950s, capsaicin was associated with pain. By 1997, Caterina et al successfully cloned the capsaicin receptor and named it vanillaid recepter subtype1(VR1) and proved to be a selective cation channel. Capsaicin causes TRPV1 to open, thereby sensing the Ca2+ influx of neurons, accompanied by the release of certain excitatory amino acids and neuropeptides, such as substance P, calcitonin gene-related peptide (CGRP). The opening of TRPV1 mediates the thermopathic stimulation signal, and the long-term effects of capsaicin can lead to calcium accumulation leading to cell death. These painful stimuli of heat or acid, in addition to acting on nociceptors, can also cause the release of activator ATP and bradykinin production. Puntambekar et al reported that the expression of TRPV1 helps maintain peripheral nerve cell integrity and sense pain. It is currently being investigated whether TRPV1 receptor antagonists can be used clinically as analgesics. However, the continued use of capsaicin can cause desensitization, and the mechanism of analgesia needs to be further elucidated. Capsaicin-induced desensitization is associated with phosphorylation of calmodulin, which is like the adrenergic receptor's phosphorylation of opioid receptors leading to desensitization of opioids. Some TRPs (mainly TRPV and TRPN protein families) are mechanically sensitive ion channels. By sensing changes in the surface stress of the cell membrane, extracellular mechanical signals are transduced intracellularly, involving auditory and tactile sensations. Mechanical stimulation transduction occurs on sensory cells of muscles, skin, and joints. TRPV4 is specifically expressed in the cochlear hair cells, the sensory nerve endings, and the sensory nerve central synapse-linked tentacles Merkelcells. TRPV4 can cause Src tyrosine phosphorylation of stretch receptors by low osmotic pressure, and has Ca2+, Mg2+ permeability, which can be activated by cell swelling, heat, phorbol ester, endogenous ligand. The inner ear hair cells are sensitive to sound vibrations and head movements, which deflect the hair bundles of the hair cells, causing the non-selective cation channels to open, resulting in depolarization of the membrane. When the bundle is continuously deflected, the channel is closed due to Ca2+ dependent adaptation. TRPV4 mechanically induces Ca2+ entry in vascular endothelial cells, most likely by shear stress-mediated Ca2+ influx. The spatial location perception mechanism of the body has always been an area of interest. TRP-4 is a homologue of the TRPN channel in C. elegans, which has 40% sequence identity, and TRP-4 is a mechanically sensitive channel for detecting zebrafish hair cells and is required for Drosophila sensation to be affected by bristles. TRP-4 is expressed in both dopamine neurons and interneurons and is abundant in dopamine neurons, which can sense mechanical stress. Li et al. 2006 showed that the “self-feeling” that controls the posture and position of the body during nematode movement requires specific neurons and TRP ion channels. This neuron of nematodes is functionally like human muscle spindles and Golgi tendon bodies, which are important organs that control the movement of the extremities. Feedback from these self-receptors can positively and negatively regulate muscle activity. The study showed that when nematodes encounter food (bacteria), they reduce body flexion and extension, so that the trp4 mutant nematode moves at maximum flexion and extension, while the wild type only occurs when there is no bacterial obstruction. The TRPML protein in the TRP protein family plays an important role in light transmission in invertebrates such as Drosophila. Light causes a conformational change in rhodopsin, which activates the G protein-mediated PLC pathway, which is mediated by a complex of TRP, and many TRP family members are present in complexes containing multiple signal components. The Drosophila signaling complex was first discovered in Drosophila photoreceptor cells, and the scaffolding molecule of this signaling complex is inactivated without post-potential D protein, and directly binds to seven protein aggregates that function in light energy conversion. Since the light-dependent cation inflow is a transient (millisecond) process, the assembly of the optical signal complex also requires a fast response. Wanget al reported that TRP nonsense mutations can cause visual signal transduction damage, INAD mislocalization and retinal deterioration, whereas knockdown of INAD binding sites on TRP has no effect on the activation process, so TRP and INAD direct binding is not required for photoreaction but does not exclude that the mutated TRP binds indirectly to the signal complex and that the interaction contributes to channel activation.

Reference:

  1. Sozucan Y, et al. TRP genes family expression in colorectal cancer. Experimental Oncology. 2015, 37(3):208-12.
  2. Julius D. TRP channels and pain. Annual Review of Cell & Developmental Biology. 2013, 29(1):355-384.
  3. Nazıroğlu M, Demirdaş A. Psychiatric Disorders and TRP Channels: Focus on Psychotropic Drugs. Current Neuropharmacology. 2015, 13(2).
  4. Smani T, et al. Functional and physiopathological implications of TRP channels. BBA - Molecular Cell Research. 2015, 1853(8):1772-1782.
  5. Jardin I, et al. Pharmacology of TRP channels in the vasculature. Current Vascular Pharmacology. 2013, 11(4).

Research Area

OUR PROMISE TO YOU Guaranteed product quality expert customer support

Inquiry Basket