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

Research output: Contribution to journalArticle

Abstract

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.

Details

Authors
  • Tabea C. Fricke
  • Frank Echtermeyer
  • Johannes Zielke
  • Jeanne de la Roche
  • Milos R. Filipovic
  • Stéphane Claverol
  • Christine Herzog
  • Makoto Tominaga
  • Ruth A. Pumroy
  • Vera Y. Moiseenkova-Bell
  • Peter M. Zygmunt
  • Andreas Leffler
  • Mirjam J. Eberhardt
Organisations
External organisations
  • Hannover Medical School
  • University of Bordeaux
  • University of Pennsylvania
  • National Institutes of Natural Sciences
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Physiology

Keywords

  • Methionine, Oxidation, Phagocytosis, Redox sensitivity, TRPV2
Original languageEnglish
Pages (from-to)24359-24365
Number of pages7
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number48
Publication statusPublished - 2019
Publication categoryResearch
Peer-reviewedYes