Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
J Neurosci
2007 Nov 21;2747:12797-807. doi: 10.1523/JNEUROSCI.2324-07.2007.
Show Gene links
Show Anatomy links
Uncoupling proton activation of vanilloid receptor TRPV1.
Ryu S
,
Liu B
,
Yao J
,
Fu Q
,
Qin F
.
???displayArticle.abstract???
Multimodal gating is an essential feature of many TRP ion channels, enabling them to respond to complex cellular environments. TRPV1, a pain receptor involved in nociception at the peripheral nerve terminals, can be activated by a range of physical and chemical stimuli (e.g., capsaicin, proton, and heat) and further sensitized by proinflammatory substances. How a single receptor achieves this multiplicity of functionality is poorly understood at the molecular level. Here, we investigated the structural basis of proton activation of TRPV1. Chimeric channels between rTRPV1 and the low pH-insensitive homolog TRPV2 were constructed by systematically exchanging the extracellular domains and were characterized using whole-cell recording in transiently transfected HEK293 cells. Two discrete domains, one involving the pore helix and the other the S3-S4 linker, were found crucial for direct activation of the channel by low pH. Single residue mutations in either domain (T633A/V538L) abrogated the proton-evoked current while preserving the capsaicin and heat responses and their potentiation by mildly acidic pH. Both residues exert a gating effect through hydrophobic interactions. Our results unravel novel information on the structural basis of channel function, and support the existence of discrete domains for multimodal gating of the channel. In view of the resemblance of the pore of TRPV1 to KcsA, our findings also provide evidence on the pore helix as an active component in channel gating in addition to its role in ion permeation.
Alagem,
The pore helix is involved in stabilizing the open state of inwardly rectifying K+ channels.
2003, Pubmed,
Xenbase
Alagem,
The pore helix is involved in stabilizing the open state of inwardly rectifying K+ channels.
2003,
Pubmed
,
Xenbase
Baumann,
Extracellular protons both increase the activity and reduce the conductance of capsaicin- gated channels.
2000,
Pubmed
Baumann,
Responses of adult human dorsal root ganglion neurons in culture to capsaicin and low pH.
1996,
Pubmed
Becchetti,
Cyclic nucleotide-gated channels. Pore topology studied through the accessibility of reporter cysteines.
1999,
Pubmed
,
Xenbase
Bevan,
Protons activate a cation conductance in a sub-population of rat dorsal root ganglion neurones.
1991,
Pubmed
Caterina,
Impaired nociception and pain sensation in mice lacking the capsaicin receptor.
2000,
Pubmed
Caterina,
The capsaicin receptor: a heat-activated ion channel in the pain pathway.
1997,
Pubmed
,
Xenbase
Caterina,
A capsaicin-receptor homologue with a high threshold for noxious heat.
1999,
Pubmed
,
Xenbase
Chou,
Resiniferatoxin binds to the capsaicin receptor (TRPV1) near the extracellular side of the S4 transmembrane domain.
2004,
Pubmed
Davis,
Vanilloid receptor-1 is essential for inflammatory thermal hyperalgesia.
2000,
Pubmed
Dodier,
Outer pore topology of the ECaC-TRPV5 channel by cysteine scan mutagenesis.
2004,
Pubmed
,
Xenbase
Doyle,
The structure of the potassium channel: molecular basis of K+ conduction and selectivity.
1998,
Pubmed
García-Martínez,
Identification of an aspartic residue in the P-loop of the vanilloid receptor that modulates pore properties.
2000,
Pubmed
,
Xenbase
Gavva,
Molecular determinants of vanilloid sensitivity in TRPV1.
2004,
Pubmed
Gonzalez,
Modulation of the Shaker K(+) channel gating kinetics by the S3-S4 linker.
2000,
Pubmed
,
Xenbase
Guex,
SWISS-MODEL and the Swiss-PdbViewer: an environment for comparative protein modeling.
1997,
Pubmed
Hui,
Capsaicin activation of the pain receptor, VR1: multiple open states from both partial and full binding.
2003,
Pubmed
,
Xenbase
Jordt,
Acid potentiation of the capsaicin receptor determined by a key extracellular site.
2000,
Pubmed
Klionsky,
A polyclonal antibody to the prepore loop of transient receptor potential vanilloid type 1 blocks channel activation.
2006,
Pubmed
Kress,
Low pH facilitates capsaicin responses in isolated sensory neurons of the rat.
1996,
Pubmed
Kuzhikandathil,
Functional analysis of capsaicin receptor (vanilloid receptor subtype 1) multimerization and agonist responsiveness using a dominant negative mutation.
2001,
Pubmed
Liu,
Change of pore helix conformational state upon opening of cyclic nucleotide-gated channels.
2000,
Pubmed
,
Xenbase
Liu,
Thermodynamics of heat activation of single capsaicin ion channels VR1.
2003,
Pubmed
,
Xenbase
Liu,
Inhibitory modulation of distal C-terminal on protein kinase C-dependent phospho-regulation of rat TRPV1 receptors.
2004,
Pubmed
,
Xenbase
Martenson,
Potentiation of rabbit trigeminal responses to capsaicin in a low pH environment.
1994,
Pubmed
Petersen,
Effect of protons on the inward current evoked by capsaicin in isolated dorsal root ganglion cells.
1993,
Pubmed
Ryu,
Low pH potentiates both capsaicin binding and channel gating of VR1 receptors.
2003,
Pubmed
Simone,
Sensitization of cat dorsal horn neurons to innocuous mechanical stimulation after intradermal injection of capsaicin.
1989,
Pubmed
Steen,
Sustained graded pain and hyperalgesia from harmless experimental tissue acidosis in human skin.
1993,
Pubmed
Tominaga,
The cloned capsaicin receptor integrates multiple pain-producing stimuli.
1998,
Pubmed
,
Xenbase
Welch,
The activation mechanism of rat vanilloid receptor 1 by capsaicin involves the pore domain and differs from the activation by either acid or heat.
2000,
Pubmed
,
Xenbase
Yang,
How does the W434F mutation block current in Shaker potassium channels?
1997,
Pubmed
,
Xenbase
Yeh,
Conformational changes of pore helix coupled to gating of TRPV5 by protons.
2005,
Pubmed
