title: C-terminal dimerization activates the nociceptive transduction channel transient receptor potential vanilloid 1.
abstract: Covalent modification of the specific cysteine residue(s) by oxidative stress robustly potentiates transient receptor potential vanilloid 1 (TRPV1) and sensitizes nociception. Here we provide biochemical evidence of dimerization of TRPV1 subunits upon exposure to phenylarsine oxide and hydrogen peroxide (H(2)O(2)), two chemical surrogates of oxidative stress. A disulfide bond formed between apposing cysteines ligates two C termini, serving as the structural basis of channel sensitization by oxidative covalent C-terminal modification. Systematic cysteine scanning of the C terminus of a cysteineless TRPV1 channel revealed a critical region within which any cysteine introduced phenylarsine oxide activation to mutant TRPV1. Oxidative sensitization persisted even when this region is substituted with a random peptide linker containing a single cysteine. So did insertion of this region to TRPV3, a homolog lacking the corresponding region and resistant to oxidative challenge. These results suggest that the non-conserved linker in the TRPV1 C terminus senses environmental oxidative stress and adjusts channel activity during cumulative oxidative damage by lowering the activation threshold of gating elements shared by TRPV channels.
authors.affiliation: Department of Biomedical Sciences, Cornell University, Ithaca, New York 14853, USA.
authors.forename: Shu
authors.initials: S
authors.lastname: Wang
authors.forename: Huai-hu
authors.initials: HH
authors.lastname: Chuang
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D001152:Arsenicals / Q000494:pharmacology; D002462:Cell Membrane / Q000378:metabolism; D002645:Chickens; D003545:Cysteine; D057809:HEK293 Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008969:Molecular Sequence Data; D009154:Mutation; D059225:Nociception / Q000187:drug effects; D010084:Oxidation-Reduction; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D021122:Protein Subunits / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D013438:Sulfhydryl Compounds / Q000737:chemistry; D050916:TRPV Cation Channels / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
chemical_list: D001152:Arsenicals; D010446:Peptide Fragments; D021122:Protein Subunits; D013438:Sulfhydryl Compounds; D050916:TRPV Cation Channels; C029341:oxophenylarsine; D006861:Hydrogen Peroxide; D003545:Cysteine