Cyclic ADP-ribose and hydrogen peroxide synergize with ADP-ribose in the activation of TRPM2 channels

Mol Cell. 2005 Apr 1;18(1):61-9. doi: 10.1016/j.molcel.2005.02.033.


The melastatin-related transient receptor potential channel TRPM2 is a plasma membrane Ca2+-permeable cation channel that is activated by intracellular adenosine diphosphoribose (ADPR) binding to the channel's enzymatic Nudix domain. Channel activity is also seen with nicotinamide dinucleotide (NAD+) and hydrogen peroxide (H2O2), but their mechanisms of action remain unknown. Here, we identify cyclic adenosine diphosphoribose (cADPR) as an agonist of TRPM2 with dual activity: at concentrations above 100 microM, cADPR can gate the channel by itself, whereas lower concentrations of 10 microM have a potentiating effect that enables ADPR to gate the channel at nanomolar concentrations. ADPR's breakdown product adenosine monophosphate (AMP) specifically inhibits ADPR, but not cADPR-mediated gating of TRPM2, whereas the cADPR antagonist 8-Br-cADPR exhibits the reverse block specificity. Our results establish TRPM2 as a coincidence detector for ADPR and cADPR signaling and provide a functional context for cADPR as a second messenger for Ca2+ influx.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenosine Monophosphate / pharmacology
  • Calcium / metabolism
  • Calcium Signaling
  • Cell Line
  • Cyclic ADP-Ribose / analogs & derivatives*
  • Cyclic ADP-Ribose / metabolism
  • Cyclic ADP-Ribose / pharmacology*
  • Humans
  • Hydrogen Peroxide / pharmacology*
  • Ion Channel Gating / drug effects
  • Ion Channel Gating / physiology
  • Ion Channels / genetics
  • Ion Channels / metabolism*
  • Kidney
  • Membrane Potentials / physiology
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Patch-Clamp Techniques
  • TRPM Cation Channels


  • 8-bromo-cyclic-ADP-ribose
  • Ion Channels
  • Membrane Proteins
  • TRPM Cation Channels
  • TRPM2 protein, human
  • Cyclic ADP-Ribose
  • Adenosine Monophosphate
  • Hydrogen Peroxide
  • Calcium