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2'-Deoxyadenosine 5'-diphosphoribose is an endogenous TRPM2 superagonist
Ralf Fliegert1, Andreas Bauche1, Adriana-Michelle Wolf Pérez1
1The Calcium Signalling Group, Department of Biochemistry and Molecular Cell Biology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.
Nature Chemical Biology
|July 4, 2017
Summary
Researchers discovered that 2'-deoxy-adenosine 5'-diphosphoribose (2'-deoxy-ADPR) is a potent activator of the TRPM2 channel, significantly exceeding the activity of previously known agonists like adenosine 5'-diphosphoribose (ADPR). This finding reveals a new signaling molecule involved in cellular responses.
Area of Science:
- Ion channel physiology
- Cell signaling
- Biochemistry
Background:
- Transient receptor potential melastatin 2 (TRPM2) channels regulate calcium (Ca2+) influx.
- TRPM2 activation by stimuli like reactive oxygen species can lead to apoptosis.
- Adenosine 5"-diphosphoribose (ADPR) was considered the primary TRPM2 agonist.
Purpose of the Study:
- To identify novel endogenous agonists for the TRPM2 channel.
- To characterize the potency and mechanism of action of potential TRPM2 agonists.
Main Methods:
- Whole-cell patch-clamp electrophysiology to measure TRPM2 channel activity.
- High-performance liquid chromatography (HPLC) and mass spectrometry for endogenous metabolite detection.
- In vitro enzymatic assays to study metabolite synthesis.
Main Results:
- 2 -deoxy-ADPR demonstrated significantly higher potency (10.4-fold) as a TRPM2 agonist compared to ADPR.
- Enhanced TRPM2 activity by 2 -deoxy-ADPR was attributed to reduced inactivation and increased open probability.
- Endogenous 2 -deoxy-ADPR was detected in Jurkat T lymphocytes and its synthesis pathway involving NMNAT-2 and CD38 was elucidated.
Conclusions:
- 2 -deoxy-ADPR is a potent endogenous TRPM2 superagonist.
- This discovery identifies a novel signaling molecule with potential roles in cellular processes.
- Further research is warranted to explore the physiological and pathophysiological implications of 2 -deoxy-ADPR-mediated TRPM2 activation.
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