Referenced in: none

Automatically associated channels: TRP , TRPV , TRPV1 , TRPV3

Title: C-terminal dimerization activates the nociceptive transduction channel transient receptor potential vanilloid 1.

Authors: Shu Wang, Huai-Hu Chuang

Journal, date & volume: J. Biol. Chem., 2011 Nov 25 , 286, 40601-7

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/21926175

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.