Research Area

TRPV


Introduction of TRPV

Transient receptor potenital (TRP) is a large family of non-selective cation channels located on the cell membrane. One type of channel can be activated by Vanillic acid compounds, so this type of channel is called the TRPV subfamily. Mutations in TRPV are associated with neurodegenerative diseases, skeletal dysplasia, kidney disease and cancer and TRPV is an important therapeutic target for these diseases. The role of TRPV1, TRPV2 and TRPV3 as thermoreceptors and the role of TRPV4 as a mechanoreceptor have important clinical implications; reducing the sensitivity to stimuli by targeting ion channels involved in thermal, chemical and mechanical sensations can alleviate chronic pain. For example, the use of a TRPV1 agonist may inhibit nociception at TRPV1, particularly in pancreatic tissue with high expression of TRPV1. The TRPV1 agonist capsaicin found in pepper has been shown to alleviate neuropathic pain, and TRPV1 agonists can inhibit noxious analgesia. So now the study of the TRPV family is of great significance.

The family members of TRPV family and their structures

Six family members of the TRPV family (TRPV1-6) are now found. Functional TRPV ion channels are structurally homotetramers or heterotetramers, and the four subunits are symmetrically arranged around the ion conducting holes. Although the degree of heteromorphism has been the subject of some debates, recent research in this field suggests that all four thermosensitive TRPVs (1-4) can form isomers with each other. This result is consistent with the general observation that TRP co-assembly tends to occur between subunits with high sequence similarity. How the TRP subunit recognizes and interacts is unclear. The TRPV channel monomer subunit components each comprise six transmembrane (TM) domains (designated S1-S6) with a pore domain between the fifth (S5) and sixth (S6) regions. The TRPV subunit contains three to five N-terminal ankyrin repeats.

Research status of TRPV family and their clinical application

TRPV1 has been identified as involved in epilepsy, with a 2-3% incidence of epilepsy worldwide. However, current antiepileptic drugs are only capable of local control of epilepsy. The aggregation of calcium ions in hippocampal neurons is a major factor in the pathogenesis of epilepsy. TRPV1 is a channel that permeates calcium ions and is the main mediator of hippocampal epilepsy. It is expressed in the hippocampal CA1 region and dentate gyrus. Studies have shown that activation of TRPV1 by oxidative stress, resin toxins, cannabinoid receptor activators or capsaicin can produce epileptic effects, which can be achieved by capsaicin, iodoresin toxin, reductin, and cannabinoid receptor antagonists. In the hippocampal cells of mice, capsaicin and iodo resin toxin can reduce transient excitatory synaptic transmission through regulation of the glutamine system and desensitization of TRPV1. In summary, current studies indicate that calcium ion accumulation through the TRPV1 channel is one of the causes of epilepsy, and inhibition of TRPV1 channels in hippocampal cells may be a target for the prevention of epilepsy. Breast cancer is one of the most common cancers affecting women. TRPV1 plays an important role in the development of breast cancer. In 2016, Weber LVet al. analyzed the expression profile of human TRP channels in 11 different breast cancer tissues and 49 cell lines and found TRPV1 channels in almost every mammary gland, and found the activation of TRPV1 channel in SUM149PT cells of Sanyin breast cancer cell model, and SUM149PT cell proliferation was significantly reduced and cell morphology changed; ligand capsaicin-activated TRPV1 receptor significantly inhibited the growth of breast cancer cells, and induced breast cancer cells apoptosis and necrosis; capsaicin can promote the apoptosis of breast cancer cells, and can also inhibit the growth of cancer cells by blocking the cell cycle of different types of cancer cells, but does not damage the growth of normal cells. Thus, the TRPV1 channel can be used as a new drug target for the treatment of breast cancer, even for highly invasive breast cancer subtypes. TRPVl-TRPV6 is a member of TRPV, and TRPV5 and TRPV6 are involved in calcium metabolism and regulation. TRPV5 is a channel that mediates the transport of calcium across the cell membrane and regulates urinary calcium levels, which may cause hypercalciuria, but the specific mechanism remains unclear. Active absorption of calcium is mainly located in the distal convoluted tubules and collecting ducts of the kidney. The posterior half of the distal convoluted tubules (DCT2) and collecting ducts (CNTs) are involved in urinary calcium reabsorption and are the sites of calcium-regulating hormones, and TRPV5 is expressed in both areas. In mice with loss of TRPV5 expression, the renal trachea and collecting ducts significantly reduced calcium ion reabsorption, and mice with TRPV5 knockout showed that their urinary calcium excretion was 6 times higher than that of the normal group, suggesting that TRPV5 deficiency can lead to high urinary calcium. TRPV5 plays a key role in the regulation of urinary calcium levels. Yanget al produced a PHAII animal model by WNK knockout mice to detect calbindin-D28k (CBP-D28k) expression in distal convoluted tubules, suggesting that TRPV5 knockout mice significantly expressed CBP-D28k, which they believe is the up-regulation of CBP-D28k expression by TRPV5, which is responsible for hypercalciuria in the PHAII model. Studies on hereditary high-calcium calcium stone model showed that the expression level of trpv5 gene and protein was lower than that of normal control rats, but the level of urinary calcium was higher than that of the control group. Thus, TRPV5 is an important channel for calcium ion reabsorption in urine. The expression of TRPV5 is negatively correlated with the incidence of urinary calculi. The lack or decrease in expression can produce hypercalciuria, and most patients with kidney stones have high urinary calcium. It is speculated that the decrease in TRPV5 expression leads to an increase in urinary calcium concentration, which may be one of the factors that form calcium-containing stones.

Reference:

  1. Thies J, Neutzler V, O’Leary F,et al. Differential Effects of TRPA and TRPV Channels on Behaviors of Caenorhabditis elegans. Journal of Experimental Neuroscience. 2016, 10(10):71-75.
  2. Zermoglio P F, Latorre-Estivalis J M, Crespo J E, et al. Thermosensation and the TRPV channel in Rhodnius prolixus. Journal of Insect Physiology. 2015, 81:145-156.
  3. Matsuura K, Seta H, Haraguchi Y, et al. TRPV-1-mediated elimination of residual iPS cells in bioengineered cardiac cell sheet tissues. Scientific Reports. 2016, 6:21747.
  4. Huynh K W, Cohen M R, Chakrapani S, et al. Structural Insight into the Assembly of TRPV Channels. Structure. 2014, 22(2):260-268.

Randhawa P K, Jaggi A S. Gadolinium and ruthenium red attenuate remote hind limb preconditioning-induced cardioprotection: possible role of TRP and especially TRPV channels. Naunyn-Schmiedeberg's archives of pharmacology. 2016, 389(8):1-10.

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