TRPing up reperfusion: neutrophil TRPM2 channels exacerbate necrosis and contractile dysfunction in post-ischaemic myocardium

Abstract

This editorial refers to ‘Neutrophil TRPM2 channels are implicated in the exacerbation of myocardial ischaemia/reperfusion injury’ by T. Hiroi et al ., pp. 271–281, this issue. Myocardial infarction, stroke, and other ischaemic disorders are leading causes of morbidity and mortality. As a consequence, intensive research efforts have been directed at determining the mechanisms underlying cell death and dysfunction induced by ischaemia. Although reperfusion is essential to rescue ischaemic tissues, re-establishing the blood supply is not without peril as it can provoke overproduction of reactive oxygen and nitrogen species (ROS, RNS), inflammation, and an excessive rise in intracellular calcium levels as common triggers for cell dysfunction and death in post-ischaemic tissues. Thus, oxidative/nitrosative stress, neutrophils, other immunocytes, and calcium overload are now recognized as key contributors to the reperfusion-induced component of total tissue injury sustained in organs subjected to ischaemia/reperfusion (I/R).1 Although a number of calcium channels have been implicated in I/R, recent work has focused attention on the potential role of redox-sensitive transient receptor potential melastatin 2 (TRPM2) channels as novel mediators.1–5 These channels consist of six transmembrane domains and intracellular N and C termini that form monovalent cation channels with selectivity for Ca2+ and to a lesser extent Mg2+.2–5 TRPM2 channels are expressed by a variety of cells and together with TRPM6 and TRPM7 are unique among ion channels in that their C-terminus contains enzymatic domains that exhibit ADP ribose (ADPR) pyrophosphatase activity, providing this domain with a site for ADPR binding and activation of the channel.2–5 With regard to mechanisms relevant to I/R, TRPM2 channels are also activated by direct oxidation of channel moieties by H2O2 or indirectly via activation of enzymatic pathways [poly(ADPR) polymerase (PARP), poly(ADPR) glycohydrolase, or the NAD/cADPR glycohydrolases CD38 …