Accumulation of Free ADP-ribose from Mitochondria Mediates Oxidative Stress-induced Gating of TRPM2 Cation Channels
Copyright policy )Accumulation of Free ADP-ribose from Mitochondria Mediates Oxidative Stress-induced Gating of TRPM2 Cation Channels
TRPM2 is a member of the transient receptor potential melastatin-related (TRPM) family of cation channels, which possesses both ion channel and ADP-ribose hydrolase functions. TRPM2 has been shown to gate in response to oxidative and nitrosative stresses, but the mechanism through which TRPM2 gating is induced by these types of stimuli is not clear. Here we show through structure-guided mutagenesis that TRPM2 gating by ADP-ribose and both oxidative and nitrosative stresses requires an intact ADP-ribose binding cleft in the C-terminal nudix domain. We also show that oxidative/nitrosative stress-induced gating can be inhibited by pharmacological reagents predicted to inhibit NAD hydrolysis to ADP-ribose and by suppression of ADP-ribose accumulation by cytosolic or mitochondrial overexpression of an enzyme that specifically hydrolyzes ADP-ribose. Overall, our data are most consistent with a model of oxidative and nitrosative stress-induced TRPM2 activation in which mitochondria are induced to produce free ADP-ribose and release it to the cytosol, where its subsequent accumulation induces TRPM2 gating via interaction within a binding cleft in the C-terminal NUDT9-H domain of TRPM2.
- Fred Hutchinson Cancer Research Center United States
- National Jewish Health United States
- University of Groningen Netherlands
- University of Mary United States
- University of Washington United States
Models, Molecular, Niacinamide, PERMEABILITY TRANSITION, Molecular Sequence Data, PYRIDINE-NUCLEOTIDE HYDROLYSIS, SIGNAL-TRANSDUCTION, TRPM Cation Channels, POLY(ADP-RIBOSE) POLYMERASE, Ion Channels, Cell Line, HYDROGEN-PEROXIDE, Humans, Amino Acid Sequence, BIOLOGICAL EVALUATION, Pyrophosphatases, NITRO-N-NITROSOGUANIDINE, Adenosine Diphosphate Ribose, Membrane Proteins, Oxidants, Reactive Nitrogen Species, Mitochondria, Protein Structure, Tertiary, ISCHEMIC INJURIES, Oxidative Stress, CELL-DEATH, Mutation, Calcium, NICOTINAMIDE-ADENINE-DINUCLEOTIDE, Reactive Oxygen Species, Ion Channel Gating
Models, Molecular, Niacinamide, PERMEABILITY TRANSITION, Molecular Sequence Data, PYRIDINE-NUCLEOTIDE HYDROLYSIS, SIGNAL-TRANSDUCTION, TRPM Cation Channels, POLY(ADP-RIBOSE) POLYMERASE, Ion Channels, Cell Line, HYDROGEN-PEROXIDE, Humans, Amino Acid Sequence, BIOLOGICAL EVALUATION, Pyrophosphatases, NITRO-N-NITROSOGUANIDINE, Adenosine Diphosphate Ribose, Membrane Proteins, Oxidants, Reactive Nitrogen Species, Mitochondria, Protein Structure, Tertiary, ISCHEMIC INJURIES, Oxidative Stress, CELL-DEATH, Mutation, Calcium, NICOTINAMIDE-ADENINE-DINUCLEOTIDE, Reactive Oxygen Species, Ion Channel Gating
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