1.A.4.2.13
TrpV1 of 839 aas and ~ 6 TMSs. Molecular determinants of vanilloid sensitivity have been examined (Gavva et al. 2004).  Ligand-activated non-selective calcium permeant cation channel involved in detection of noxious chemical and thermal stimuli. TRPV1 channels are present in odontoblasts, suggesting that odontoblasts may directly respond to noxious stimuli such as a thermal-heat stimulus (Okumura et al. 2005). It may mediate proton influx and be involved in intracellular acidosis in nociceptive neurons. It is also involved in mediating inflammatory pain and hyperalgesia (Benemei et al. 2015).  The 3.4 Å resolution structure shows that the overall fold is the same as for voltage-gated ion channels (TC# 1.A.1) (Liao et al. 2013). Capsaicin-induced apoptosis in glioma cells is mediated by TRPV1 (Amantini et al. 2007). Capsaicin binds to a pocket formed by the channel's TMSs, where it takes a ""tail-up, head-down"" configuration. Binding is mediated by both hydrogen bonds and van der Waals interactions. Upon binding, capsaicin stabilizes the open state of TRPV1 by ""pull-and-contact"" with the S4-S5 linker (Yang and Zheng 2017). Several protein kinases, including PKD1 (protein kinase D1), Cdk5 (cyclin-dependent kinase 5) and LIMK (LIM- motif containing kinase) regulate TRPV1 and inflammatory thermal hyperalgesia (Zhang and Wang 2017). TrpV1 and TrpA1 are inflammatory mediators causing cutaneous chronic itch in several diseases (Xie and Li 2018). The locations and characteristics of volatile general anesthetic binding sites in the transmembrane domain of TRPV1 have been examined (Jorgensen and Domene 2018). The TRPV1 ion channel is a neuronal sensor that plays an important role in nociception and neuropathic as well as inflammatory pain. In clinical trials, hyperthermia and thermo-hypoaesthesia are major side effects of TRPV1 antagonists (Damann et al. 2020). The TRPV1 ion channel is a polymodal sensor integrating stimuli from molecular modulators with temperature, pH and transmembrane potential. Temperature-dependent gating may constitute the molecular basis for its role in heat sensation and body temperature regulation. Damann et al. 2020 characterized the prototypic small molecule TRPV1 inhibitors GRT12360V and GRTE16523. The oxidizing reagent copper-o-phenanthroline is an open channel blocker of TRPV1 (Tousova et al. 2004). Lack of TRPV1 aggravates obesity-associated hypertension through the disturbance of mitochondrial Ca²⁺ homeostasis in brown adipose tissue (Li et al. 2022). Lipoic/Capsaicin-related amides are TRPV1 agonists endowed with protective properties against oxidative stress (Brizzi et al. 2022). Agonistic/antagonistic properties of lactones in food flavors on the sensory ion channels, TRPV1 and TRPA1 have been reviewed (Ogawa et al. 2022). TRPV1 channel modulators provide a prospective therapy for diabetic neuropathic pain (Liu et al. 2023). Drosophila appear to possess intricate pain sensitization and modulation mechanisms similar to those in mammals (Jang et al. 2023). Barbamide enhances the effect of the TRPV1 agonist capsaicin and enhanced store-operated calcium entry (SOCE) responses in mice after depletion of intracellular calcium (Hough et al. 2023). The safety and efficacy of topical ocular SAF312 (Libvatrep) in post-photorefractive keratectomy (PRK) pain, an inhibitor of TRPV1, has been evaluated (Thompson et al. 2023). Modulation of membrane trafficking of AQP5 in the lens in response to changes in zonular tension is mediated by TRPV1 (Petrova et al. 2023). The TRPV1 channel, in addition to being associated with pain, plays a role in immune regulation, and their dysregulation frequently affects the development of rheumatoid arthritis (Qu et al. 2023). Irreversible protein unfolding, which is generally thought to be destructive to physiological function, is essential to TRPV1 thermal transduction and, possibly, to other strongly temperature-dependent processes in biology (Mugo et al. 2023).  Strong pathogenetic associations of TRPV1 with neurodegenerative diseases (NDs), in particular Alzheimer's disease (AD), Parkinson's disease (PD) and multiple sclerosis (MS) via regulating neuroinflammation have been forthcming. Therapeutic effects of TRPV1 agonists and antagoniststs on the treatment of AD and PD in animal models are emerging. Mugo et al. 2023 summarized the current understanding of TRPV1's effects and its agonists and antagonists as a therapeutic means in neurodegenerative diseases, and highlight future treatment strategies using natural TRPV1 agonists.  Increased response in TrpV1(V527M) channels to protons and enhanced sensitization by arachidonic acid metabolite 12-hydroxyeicosatetraenoic acid (12-HETE), two inflammatory mediators released in the cornea after tissue damage, may contribute to the pathogenesis of corneal neuralgia after refractive surgery (Gualdani et al. 2024).