TRPM2: a calcium influx pathway regulated by oxidative stress and the novel second messenger ADP-ribose

Abstract

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.

The NLRP3 inflammasome functions as a driver of the myelodysplastic syndrome phenotype

“…28 We show that activation of pattern recognition receptors triggers expansion in size and volume of MDS progenitors via influx of cations by membrane channels that are activated by NOX-derived ROS. [56][57][58][59] Our findings show that MDS BM-MNCs display increased influx of the membrane-impermeable cationic dye EtBr, confirming pore formation. Additionally, flow cytometry assessment of BM cell size according to lineage and stage of maturation confirmed significantly larger BM precursors in MDS patients than in normal controls that increased directly with NLRP3 mean fluorescence intensity.…”

Identification and Functional Characterization of Ion Channels in CD34+ Hematopoietic Stem Cells from Human Peripheral Blood

“…Under the whole-cell configuration with 100 µM ADPR in the Cs + -rich pipette solution, step-like increases of inward current were observed (n = 6). The unitary current amplitude (4.78 ± 0.11 pA) and the pattern of step-like increases are consistent with the single channel conductance (~80 pS) and slow kinetics of TRPM2 (Kühn et al, 2005). The inward current was completely abolished by exchanging extracellular Na + with NMDG + , a nonpermeable large cation (Fig.…”

“…To record the nonselective cation channel currents, a Cs + -rich pipette solution was used. TRPM2 is known to be primarily activated by cytosolic ADP-ribose (ADPR), and this activation is facilitated by Ca 2+ (Kühn et al, 2005). Under the whole-cell configuration with 100 µM ADPR in the Cs + -rich pipette solution, step-like increases of inward current were observed (n = 6).…”

Androgen and PARP-1 Regulation of TRPM2 Channels after Ischemic Injury

“…The calcium-permeable TRPM2 ion channel is expressed in neurons in the cortex, hippocampus, striatum, and brainstem, among other regions [1][2][3][4][5][6] and is activated after oxidative stress, induced by exogenous hydrogen peroxide. 2,[7][8][9] Transient receptor potential M2 (TRPM2) channels were initially identified and extensively characterized by our group, 7,8,10,11 and demonstrated to contribute to oxidative stress-induced cell death.…”