TRPV1

7442193034ENSG00000196689ENSMUSG00000005952Q8NER1Q704Y3NM_018727NM_080704NM_080705NM_080706NM_001001445NP_061197NP_542435NP_542436NP_542437NP_001001445The transient receptor potential cation channel subfamily V member 1 (TrpV1), also known as the capsaicin receptor and the vanilloid receptor 1, is a protein that, in humans, is encoded by the TRPV1 gene. It was the first isolated member of the transient receptor potential vanilloid receptor proteins that in turn are a sub-family of the transient receptor potential protein group. This protein is a member of the TRPV group of transient receptor potential family of ion channels. The transient receptor potential cation channel subfamily V member 1 (TrpV1), also known as the capsaicin receptor and the vanilloid receptor 1, is a protein that, in humans, is encoded by the TRPV1 gene. It was the first isolated member of the transient receptor potential vanilloid receptor proteins that in turn are a sub-family of the transient receptor potential protein group. This protein is a member of the TRPV group of transient receptor potential family of ion channels. The function of TRPV1 is detection and regulation of body temperature. In addition, TRPV1 provides a sensation of scalding heat and pain (nociception). TRPV1 is a nonselective cation channel that may be activated by a wide variety of exogenous and endogenous physical and chemical stimuli. The best-known activators of TRPV1 are: temperature greater than 43 °C (109 °F); acidic conditions; capsaicin (the irritating compound in hot chili peppers); and allyl isothiocyanate, the pungent compound in mustard and wasabi. The activation of TRPV1 leads to a painful, burning sensation. Its endogenous activators include: low pH (acidic conditions), the endocannabinoid anandamide, N-oleyl-dopamine, and N-arachidonoyl-dopamine. TRPV1 receptors are found mainly in the nociceptive neurons of the peripheral nervous system, but they have also been described in many other tissues, including the central nervous system. TRPV1 is involved in the transmission and modulation of pain (nociception), as well as the integration of diverse painful stimuli. The sensitivity of TRPV1 to noxious stimuli, such as high temperatures, is not static. Upon tissue damage and the consequent inflammation, a number of inflammatory mediators, such as various prostaglandins and bradykinin, are released. These agents increase the sensitivity of nociceptors to noxious stimuli. This manifests as an increased sensitivity to painful stimuli (hyperalgesia) or pain sensation in response to non-painful stimuli (allodynia). Most sensitizing pro-inflammatory agents activate the phospholipase C pathway. Phosphorylation of TRPV1 by protein kinase C have been shown to play a role in sensitization of TRPV1. The cleavage of PIP2 by PLC-beta can result in disinhibition of TRPV1 and, as a consequence, contribute to the sensitivity of TRPV1 to noxious stimuli. Upon prolonged exposure to capsaicin, TRPV1 activity decreases, a phenomenon called desensitization. Extracellular calcium ions are required for this phenomenon, thus influx of calcium and the consequential increase of intracellular calcium mediate this effect. Various signaling pathways such as calmodulin and calcineurin, and the decrease of PIP2, have been implicated in desensitization of TRPV1. Desensitization of TRPV1 is thought to underlie the paradoxical analgesic effect of capsaicin. Treatment of pain is an unmet medical need costing billions of dollars every year. As a result of its involvement in nociception, TRPV1 has been a prime target for the development of novel pain reducers (analgesics). Two major strategies have been used: Antagonists block TRPV1 activity, thus reducing pain. Identified antagonists include the competitive antagonist capsazepine and the non-competitive antagonist ruthenium red. These agents could be useful when applied systemically. Numerous TRPV1 antagonists have been developed by pharmaceutical companies. TRPV1 antagonists have shown efficacy in reducing nociception from inflammatory and neuropathic pain models in rats. This provides evidence that TRPV1 is capsaicin's sole receptor. In humans, drugs acting at TRPV1 receptors could be used to treat neuropathic pain associated with multiple sclerosis, chemotherapy, or amputation, as well as pain associated with the inflammatory response of damaged tissue, such as in osteoarthritis. The major roadblock for the usefulness of these drugs is their effect on body temperature (hyperthermia). The role of TRPV1 in the regulation of body temperature has emerged in the last few years. Based on a number of TRPV-selective antagonists' causing an increase in body temperature (hyperthermia), it was proposed that TRPV1 is tonically active in vivo and regulates body temperature by telling the body to 'cool itself down'. Without these signals, the body overheats. Likewise, this explains the propensity of capsaicin (a TRPV1 agonist) to cause sweating (i.e.: a signal to reduce body temperature). In a recent report, it was found that tonically active TRPV1 channels are present in the viscera and keep an ongoing suppressive effect on body temperature. Recently, it was proposed that predominant function of TRPV1 is body temperature maintenance Experiments have shown that TRPV1 blockade increases body temperature in multiple species, including rodents and humans, suggesting that TRPV1 is involved in body temperature maintenance. Recently, AMG 517, a highly selective TRPV1 antagonist was dropped out of clinical trials due to the undesirable level of hyperthermia. A second molecule, SB-705498, was also evaluated in the clinic but its effect on body temperature was not reported. Recently, it was disclosed that clinical trials of two more TRPV1 antagonists, GRC 6211 and NGD 8243, have been stopped. Post translational modification of TRPV1 protein by its phosphorylation is critical for its functionality. Recent reports published from NIH suggest that Cdk5-mediated phosphorylation of TRPV1 is required for its ligand-induced channel opening. TRPV1 is activated by numerous agonists from natural sources. Agonists such as capsaicin and resiniferatoxin activate TRPV1 and, upon prolonged application, cause TRPV1 activity to decrease (desensitization), leading to alleviation of pain via the subsequent decrease in the TRPV1 mediated release of inflammatory molecules following exposures to noxious stimuli. Agonists can be applied locally to the painful area in various forms, generally as a patch or an ointment. Numerous capsaicin-containing creams are available over the counter, containing low concentrations of capsaicin (0.025 - 0.075%). It is debated whether these preparations actually lead to TRPV1 desensitization; it is possible that they act via counter-irritation. Novel preparations containing higher capsaicin concentration (up to 10%) are under clinical trials. 8% capsaicin patches have recently become available for clinical use, with supporting evidence demonstrating that a 30-minute treatment can provide up to 3 months analgesia by causing regression of TRPV1-containing neurons in the skin. Currently, these treatments must be re-administered on a regular (albeit infrequent) schedule in order to maintain their analgesic effects.