TRPM2: a calcium influx pathway regulated by oxidative stress and the novel second messenger ADP-ribose.
A unique functional property within the transient receptor potential (TRP) family of cation channels is the gating of TRP (melastatin) 2 (TRPM2) channels by ADP-ribose (ADPR). ADPR binds to the intracellular C-terminal tail of TRPM2, a domain that shows homology to enzymes with pyrophosphatase activity. Cytosolic Ca(2+) enhances TRPM2 gating by ADPR; ADPR and Ca(2+) in concert may be an important messenger system mediating Ca(2+) influx. Other stimuli of TRPM2 include NAD and H(2)O(2) and cyclic ADPR, which may act synergistically with ADPR. H(2)O(2), an experimental paradigm of oxidative stress, may also induce the formation of ADPR in the nucleus or mitochondria. In this review, we summarize the gating properties of TRPM2 and the proposed pathways of channel activation in vivo. TRPM2 is likely to be a key player in several signalling pathways, mediating cell death in response to oxidative stress or in reperfusion injury. Moreover, it plays a decisive role in experimentally induced diabetes mellitus and in the activation of leukocytes.
Kühn
Frank J P
FJ
Medical Faculty, RWTH Aachen, Institute of Physiology, Pauwelsstrasse 30, 52057 Aachen, Germany.
Heiner
Inka
I
Lückhoff
Andreas
A
D000246:Adenosine Diphosphate Ribose / Q000502:physiology*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D036563:Cyclic ADP-Ribose / Q000502:physiology; D004357:Drug Synergism; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D018384:Oxidative Stress / Q000502:physiology*; D011065:Poly(ADP-ribose) Polymerases / Q000502:physiology; D015290:Second Messenger Systems / Q000502:physiology; D050053:TRPM Cation Channels / Q000737:chemistry / Q000187:drug effects / Q000235:genetics / Q000502:physiology*
D050053:TRPM Cation Channels; C121934:TRPM2 protein, human; D036563:Cyclic ADP-Ribose; D000246:Adenosine Diphosphate Ribose; D006861:Hydrogen Peroxide; D011065:Poly(ADP-ribose) Polymerases; D002118:Calcium