1.A.4.2.1
Vanilloid receptor subtype 1 (VR1 or TRPV1) (noxious, heat-sensitive [opens with increasing temperatures; e.g., >42°C]; also sensitive to acidic pH and voltage and inflamation; serves as the receptor for the alkaloid irritant, capsaicin, for resiniferatoxin and for endo-cannabinoids (Murillo-Rodriguez et al. 2017). Resiniferatoxin binds to the capsaicin receptor (TRPV1) near the extracellular side of the S4 transmembrane domain (Chou et al. 2004). It is regulated by bradykinin and prostaglandin E2) (contains a C-terminal region, adjacent to the channel gate, that determines the coupling of stimulus sensing and channel opening) (Garcia-Sanz et al., 2007; Matta and Ahern, 2007). It is activated and sensitized by local anesthetics in sensory neurons (Leffler et al., 2008). A bivalent tarantula toxin activates the capsaicin receptor (TRPV1) by targeting the outer pore domain (Bohlen et al., 2010). Single-channel properties of TRPV1 are modulated by phosphorylation (Studer and McNaughton, 2010). TRPV1 mediates an itch associated response (Kim et al., 2011). The thermosensitive TRP channel pore turret is part of the temperature activation apparatus (Yang et al., 2010). Modular thermal sensors in temperature-gated transient receptor potential (TRP) channels have been identified (Yao et al., 2011). TRPV1 opening is associated with major structural rearrangements in the outer pore, including the pore helix and selectivity filter, as well as pronounced dilation of a hydrophobic constriction at the lower gate, suggesting a dual gating mechanism (Cao et al. 2013). Allosteric coupling between upper and lower gates may account for modulation exhibited by TRPV1 and other TRP channels (Liao et al. 2013).  TRPV1 regulates longevity and metabolism by neuropeptides in mice (Riera et al. 2014). The pore of TRPV1 contains the structural elements sufficient for activation by noxious heat (Zhang et al. 2017). In bull sperm, TRPV1 functions in the regulation of motility and the  acrosome reaction (Kumar et al. 2019). The dynamics of water in the transmembrane pore of TRPV1 have been studied (Trofimov et al. 2019). TRPV1 - 6 channel subunits do not combine arbitrarily. With the exception of TRPV5 and TRPV6, TRPV channel subunits preferentially assemble into homomeric complexes (Hellwig et al. 2005). TrpV1-gated ion channels have been used as sensors for imaging applications (Zhu et al. 2021). Capsaicin and protons differently modulate the activation kinetics of the mouse TrpV1 channel induced by depolarization (Takahashi et al. 2021). The impact of TRPV1 on cancer pathogenesis and therapy has been reviewed (Li et al. 2021). TRPV1 may be an analgesic target for patients experiencing pain after oral irradiation (Lai et al. 2021). The vanilloid (capsaicin) receptor TRPV1 functions in blood pressure regulation and may be a therapeutic target in hypertension (Szallasi 2023). Chu et al. 2023 elucidated the redox state of C387-C391 mediated long-range allostery of TRPV1, which provided new insights into the activation mechanism of TRPV1.  TRPV1 channels are players in the reticulum-mitochondria Ca²⁺ coupling in a rat cardiomyoblast cell line (Tessier et al. 2023). TRPV1 is a target for recovery from chronic pain, producing analgesic effects after its inhibition. The study of TrpV1 channel antagonists revealed possible drug design purposes (Gianibbi et al. 2024).  Galangin improves ethanol-induced gastric mucosal injuryby targetting TrpV1 (Lin et al. 2024).