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).