The distinct roles of the N-terminal and C-terminal ADP-ribose binding sites in TRPM2 channel

TRPM2 is a calcium-permeable, non-selective cation channel present in different species from unicellular Choanoflagellates to human. TRPM2 plays an important role in the survival of early species and is critically involved in diverse physiological processes including core body temperature regulation, immune response, insulin secretion, and apoptosis. TRPM2 is polymodal and can be activated by a wide range of stimuli including warm temperature, oxidative stress and NAD+-related metabolites such as ADP-ribose (ADPR). The consensus was that in the presence of calcium, ADPR activates TRPM2 upon binding to its characteristic C-terminal NUDT9-H domain. However, recent studies by our group and others have established that the N-terminal MHR1/2 domain contains a previously unknown ADPR binding site that is conserved across species and is absolutely essential for TRPM2 gating (Kühn et al., 2016, 2019; Huang et al., 2018, 2019; Tóth et al., 2020). The important role of MHR1/2 domain in channel gating is further supported by the fact that the antagonist 8-Br-cADPR inhibits the channel by binding to the MHR1/2 domain and stabilizing the channel in an apo-like conformation (Kolisek et al., 2005; Huang et al., 2019). In contrast to the conserved role of the MHR1/2 domain, the function of NUDT9-H domain has changed with evolution. In invertebrates, the NUDT9-H domain does not directly gate the channel but is indirectly involved in channel gating by hydrolyzing the agonist ADPR into AMP and ribose-5-phosphate (Kühn et al., 2016; Iordanov et al., 2019). In vertebrates, the NUDT9-H domain has no enzymatic activity, but cooperates with the MHR1/2 domain to open the channel (Iordanov et al., 2016; Huang et al., 2018, 2019).