2′-Deoxyadenosine 5′-diphosphoribose is an endogenous TRPM2 superagonist

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.

Integration of nicotinic acid adenine dinucleotide phosphate (NAADP)‐dependent calcium signalling

“…Returning to the formation of NAADP, it should also be noted that CD38 exists in two different orientations: (i) as a type II enzyme with its catalytic site facing the extracellular space (ectoenzyme) and (ii) as a type III enzyme with the reverse orientation (Zhao et al 2012). Recently, we have confirmed a type III orientation using 1,N 6 -etheno-NAD conversion to 1,N 6 -etheno-ADPR as readout (Fliegert et al 2017). The relative enzyme activity of type III CD38 compared to type II CD38, at least in Jurkat T cells, was very low.…”

“…Recently, we have confirmed a type III orientation using 1,N 6 ‐etheno‐NAD conversion to 1,N 6 ‐etheno‐ADPR as readout (Fliegert et al . ). The relative enzyme activity of type III CD38 compared to type II CD38, at least in Jurkat T cells, was very low.…”

Molecular Regulations and Functions of the Transient Receptor Potential Channels of the Islets of Langerhans and Insulinoma Cells

“…ADPR is the best known agonist of TRPM2, but a recent study reports that 2 -deoxy-ADPR is the most efficient endogenous agonist of the channel [41]. Compared to ADPR, 2 -deoxy-ADPR produces 10-fold more TRPM2 current.…”

“…2 -deoxy-ADPR is thought to be produced by CD38 from cytosolic 2'-deoxy-NAD. It has been speculated that 2 -deoxy-ADPR is the principal agonist of TRPM2 for mediating the physiological signaling functions [41]. ADPR-2'-phosphate is a partial agonist of TRPM2 that activates TRPM2 with reduced efficacy [40,41].…”

CD38, CD157, and RAGE as Molecular Determinants for Social Behavior

“…The initial free intracellular Ca 2+ concentration rise is more sensitive to Ca 2+ influx due to thermal stimulation, while ADPR and the late sustained phase are dependent on cADPR-involved Ca 2+ mobilization from the ryanodine-sensitive Ca 2+ pool. Very recently, an endogenous cADPR analogue, 2 -deoxyadenosine 5 -diphosphoribose, was documented and demonstrated to be very powerful [70]. It is of interest to test it in OT release in the hypothalamus.…”