Detrimental or beneficial: the role of TRPM2 in ischemia/reperfusion injury

Abstract

Ischemia/reperfusion (I/R) injury is the main cause of tissue damage and dysfunction. I/R injury is characterized by Ca(2+) overload and production of reactive oxygen species (ROS), which play critical roles in the process of I/R injury to the brain, heart and kidney, but the underlying mechanisms are largely elusive. Recent evidence demonstrates that TRPM2, a Ca(2+)-permeable cationic channel and ROS sensor, is involved in I/R injury, but whether TRPM2 plays a protective or detrimental role in this process remains controversial. In this review, we discuss the recent progress in understanding the role of TRPM2 in reperfusion process after brain, heart and kidney ischemia and the potential of targeting TRPM2 for the development of therapeutic drugs to treat I/R injury.

Figure 1

The topology model of TRPM2 channel. Each subunit of TRPM2 has six transmembrane (TM) spanning domains (S1–S6) with a pore-forming loop between the fifth (S5) and sixth (S6) segments. The intracellular N-terminus has four sections of TRPM subfamily homology domain (MHD) and a IQ-like motif located in the second MHD. The intracellular C-terminus contains a TRP box (TRP) and a coiled-coil domain (CCD). The distal C-terminus has an adenosine diphosphate ribose (ADPR) pyrophosphatase homolog domain (NUDT9-H).

Figure 2

TRPM2 channels in neurons, microglia and neutrophils play detrimental role in brain ischemic reperfusion injury via multiple signaling pathways.

Figure 3

(A) The schema model of TRPM2 channels mediated detrimental or protective signaling pathways in cardiac ischemic reperfusion injury; (B) TRPM2 channels play a detrimental role in renal ischemic reperfusion injury through regulating RAC1 dependent NADPH oxidase activity.