Cyclic ADP-ribose and hydrogen peroxide synergize with ADP-ribose in the activation of TRPM2 channels.
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.
Kolisek
Martin
M
Laboratory of Cell and Molecular Signaling, Center for Biomedical Research, The Queen's Medical Center, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii 96813, USA.
Beck
Andreas
A
Fleig
Andrea
A
Penner
Reinhold
R
D000249:Adenosine Monophosphate / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D002460:Cell Line; D036563:Cyclic ADP-Ribose / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism*; D007668:Kidney; D008564:Membrane Potentials / Q000502:physiology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D050053:TRPM Cation Channels
C493642:8-bromo-cyclic-ADP-ribose; D007473:Ion Channels; D008565:Membrane Proteins; D050053:TRPM Cation Channels; C121934:TRPM2 protein, human; D036563:Cyclic ADP-Ribose; D000249:Adenosine Monophosphate; D006861:Hydrogen Peroxide; D002118:Calcium