Acid potentiation of the capsaicin receptor determined by a key extracellular site.
By S. Jordt. Proceedings of the National Academy of Sciences of the United States of America, 2000
659 citations recorded by the source corpus.
The capsaicin (vanilloid) receptor, VR1, is a sensory neuron-specific ion channel that serves as a polymodal detector of pain-producing chemical and physical stimuli. The response of VR1 to capsaicin or noxious heat is dynamically potentiated by extracellular protons within a pH range encountered during tissue acidosis, such as that associated with arthritis, infarction, tumor growth, and other forms of injury. A molecular determinant for this important physiological activity was localized to an extracellular Glu residue (E600) in the region linking the fifth transmembrane domain with the putative pore-forming region of the channel. We suggest that this residue serves as a key regulatory site of the receptor by setting sensitivity to other noxious stimuli in response to changes in extracellular proton concentration. We also demonstrate that protons, vanilloids, and heat promote channel opening through distinct pathways, because mutations at a second site (E648) selectively abrogate proton-evoked channel activation without diminishing responses to other noxious stimuli. Our findings provide molecular evidence for stimulus-specific steps in VR1 activation and offer strategies for the development of novel analgesic agents.
Subfields: Molecular Biology, Sensory Systems
View Paper: https://www.semanticscholar.org/paper/e39b9a89367d8aeab4eb898567f52e6d6379aa6a
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Citations in the corpus
- Bradykinin and nerve growth factor release the capsaicin receptor from PtdIns(4,5)P2-mediated inhibition (2001, background): “Whereas extracellular protons interact directly with VR1 to potentiate its sensitivity to capsaicin or hea”
- Heat-Evoked Activation of the Ion Channel, TRPV4 (2002, background): “An analogous situation has been observed for TRPV1, in which proton-, heat-, and capsaicin-evoked responses are mechanistically distinguishable, although they interact (Jordt et al., 2000; Jordt and Julius, 2002).”
- The principle of temperature-dependent gating in cold- and heat-sensitive TRP channels (2004, background): “TRPV1 is directly gated by several chemicals that cause a burning sensation such as vanilloid compounds and proton”
- Identification of a cold receptor reveals a general role for TRP channels in thermosensation (2002, background): “Other inflammatory products, such as protons and lipids, seem to interact with VR1 directl”
- TRP channels and pain. (2013, background): “…in the vicinity of the trauma, culminating in the production and release of a complex mixture of proinflammatory and proalgesic factors (including neurotrophins, bioactive lipids, extracellular protons and nucleotides, proteases, and monoamines), collectively referred to as the inflammatory soup.”
- Mustard oils and cannabinoids excite sensory nerve fibres through the TRP channel ANKTM1 (2004, methodology): “Apparent mismatches with the ENSEMBL genomic sequence were corrected by PCR and the final product cloned into the pFROG3 mammalian/oocyte expression vecto”
- Molecular mechanisms of nociception (2001, background): “Structure–function studies have now identified several negatively charged residues within putative extracellular loops of VR1 that are important for mediating these effect”
- The TRP Superfamily of Cation Channels (2005, neutral): “TRPV1-dependent cation conductance (103, 104).”
- Molecular basis for species-specific sensitivity to "hot" chili peppers. (2002, positive): “directed mutagenesis as previously described (Jordt et al., 2000).”