2'-Deoxyadenosine 5'-diphosphoribose is an Endogenous TRPM2 Superagonist

Overview

Journal Nat Chem Biol

Specialties Biochemistry
Biology
Chemistry

Date 2017 Jul 4

PMID 28671679

Citations 50

Authors

Ralf Fliegert

Andreas Bauche

Adriana-Michelle Wolf Perez

Joanna M Watt

Monika D Rozewitz

Riekje Winzer

Mareike Janus

Feng Gu

Annette Rosche

Angelika Harneit

Marianne Flato

Christelle Moreau

Tanja Kirchberger

Valerie Wolters

Barry V L Potter

Andreas H Guse

Affiliations

Soon will be listed here.

Abstract

Transient receptor potential melastatin 2 (TRPM2) is a ligand-gated Ca-permeable nonselective cation channel. Whereas physiological stimuli, such as chemotactic agents, evoke controlled Ca signals via TRPM2, pathophysiological stimuli such as reactive oxygen species and genotoxic stress result in prolonged TRPM2-mediated Ca entry and, consequently, apoptosis. To date, adenosine 5'-diphosphoribose (ADPR) has been assumed to be the main agonist for TRPM2. Here we show that 2'-deoxy-ADPR was a significantly better TRPM2 agonist, inducing 10.4-fold higher whole-cell currents at saturation. Mechanistically, this increased activity was caused by a decreased rate of inactivation and higher average open probability. Using high-performance liquid chromatography (HPLC) and mass spectrometry, we detected endogenous 2'-deoxy-ADPR in Jurkat T lymphocytes. Consistently, cytosolic nicotinamide mononucleotide adenylyltransferase 2 (NMNAT-2) and nicotinamide adenine dinucleotide (NAD)-glycohydrolase CD38 sequentially catalyzed the synthesis of 2'-deoxy-ADPR from nicotinamide mononucleotide (NMN) and 2'-deoxy-ATP in vitro. Thus, 2'-deoxy-ADPR is an endogenous TRPM2 superagonist that may act as a cell signaling molecule.

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