Biophysics and physiological relevance of TRPM2 expression in the CNS

The mammalian TRP (transient receptor potential) channels are one of the most recently identified superfamilies of ion channels, which consists of 28 members that are organised in five subfamilies (TRPC, TRPV, TRPM, TRPP and TRPA). Members of the Melastatin-related TRPM cation channel family are expressed in excitable and non-excitable cells and its biological roles are diverse. They include sensing of second messengers, oxidative stress, cold or warm temperature, intracellular Mg²⁺ and Ca²⁺ concentrations and of various chemical compounds.

TRPM2 is a calcium-permeable, non-selective cation channel activated by the generation of oxidative stress and intracellular application of ADP-ribose (Perraud et al. 2001). Its activation by oxidative stress is thought to result from the activity of the nuclear enzyme poly(ADP-ribose) polymerase (PARP)-1 which functions as a key mediator between oxidative damage and TRPM2 activation by formation and accumulation of intracellular ADP-ribose.

The activation of TRPM2 by oxidative/nitrosative stress and the resulting Ca²⁺ entry into TRPM2-expressing cells have made this channel a potential novel target for the treatment of pathologies that involve an imbalance between the production of reactive oxygen species (ROS) and cellular defence mechanisms. The strong expression of TRPM2 throughout the CNS and the potential role of oxidative stress in its activation suggest that TRPM2 antagonists may be beneficial in other neurodegenerative conditions such as stroke, Parkinson's disease and Alzheimer's dementia.