Oxidation of methionine residues activates the high-threshold heat-sensitive ion channel TRPV2

Proc Natl Acad Sci U S A. 2019 Nov 26;116(48):24359-24365. doi: 10.1073/pnas.1904332116. Epub 2019 Nov 12.


Thermosensitive transient receptor potential (TRP) ion channels detect changes in ambient temperature to regulate body temperature and temperature-dependent cellular activity. Rodent orthologs of TRP vanilloid 2 (TRPV2) are activated by nonphysiological heat exceeding 50 °C, and human TRPV2 is heat-insensitive. TRPV2 is required for phagocytic activity of macrophages which are rarely exposed to excessive heat, but what activates TRPV2 in vivo remains elusive. Here we describe the molecular mechanism of an oxidation-induced temperature-dependent gating of TRPV2. While high concentrations of H2O2 induce a modest sensitization of heat-induced inward currents, the oxidant chloramine-T (ChT), ultraviolet A light, and photosensitizing agents producing reactive oxygen species (ROS) activate and sensitize TRPV2. This oxidation-induced activation also occurs in excised inside-out membrane patches, indicating a direct effect on TRPV2. The reducing agent dithiothreitol (DTT) in combination with methionine sulfoxide reductase partially reverses ChT-induced sensitization, and the substitution of the methionine (M) residues M528 and M607 to isoleucine almost abolishes oxidation-induced gating of rat TRPV2. Mass spectrometry on purified rat TRPV2 protein confirms oxidation of these residues. Finally, macrophages generate TRPV2-like heat-induced inward currents upon oxidation and exhibit reduced phagocytosis when exposed to the TRP channel inhibitor ruthenium red (RR) or to DTT. In summary, our data reveal a methionine-dependent redox sensitivity of TRPV2 which may be an important endogenous mechanism for regulation of TRPV2 activity and account for its pivotal role for phagocytosis in macrophages.

Keywords: TRPV2; methionine; oxidation; phagocytosis; redox sensitivity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Calcium Channels / chemistry
  • Calcium Channels / genetics
  • Calcium Channels / metabolism
  • Chloramines / chemistry
  • Escherichia coli / genetics
  • Hot Temperature
  • Humans
  • Hydrogen Peroxide / chemistry
  • Macrophages
  • Methionine / chemistry
  • Methionine / metabolism*
  • Mutation
  • Oxidants / chemistry
  • Oxidation-Reduction
  • Patch-Clamp Techniques
  • Phagocytosis
  • TRPM Cation Channels / chemistry
  • TRPM Cation Channels / metabolism
  • TRPV Cation Channels / chemistry*
  • TRPV Cation Channels / genetics
  • TRPV Cation Channels / metabolism*
  • Tosyl Compounds / chemistry


  • Calcium Channels
  • Chloramines
  • Oxidants
  • TRPM Cation Channels
  • TRPM2 protein, human
  • TRPV Cation Channels
  • TRPV2 protein, human
  • Tosyl Compounds
  • Trpv2 protein, mouse
  • Trpv2 protein, rat
  • chloramine-T
  • Methionine
  • Hydrogen Peroxide