Figure 1. TRPM2 protein structure and transmembrane topology.

A, TRPM2 protein structure. Human TRPM2 is a protein of ∼170 kDa composed of 1503 amino acids (1507 in mouse and rat). The channel's N-terminal has four homologous regions (MHR) of unknown function and a calmodulin (CaM) binding IQ-like motif, followed by six transmembrane segments (TM: S1–S6). The TRPM2 pore-forming loop domain locates between S5 and S6. The TRPM2 C-terminus contains a TRP box and a coil–coil domain (CC), and a C-terminal adenosine diphosphate ribose (ADPR) pyrophosphatase domain (Nudix-like domain or NUDT9 homology domain, NUDT9-H). B, TRPM2 transmembrane topology. The TRPM2 N- and C-termini face the cytosol. Cytosolic ADPR binds to the TRPM2 NUDT9-H region and gates the channel, allowing calcium (Ca²⁺) and sodium (Na⁺) influx. ADPR is hydrolysed to ribose 5-phosphate and adenosine monophosphate (AMP) by TRPM2 NUDT9-H enzymatic activity. TRPM2 gating by ADPR is facilitated by hydrogen (H₂O₂), cyclic ADPR (cADPR) and Ca²⁺. AMP acts as a negative regulator of TRPM2 gating by ADPR and 8Br-cADPR inhibits cADPR- and H₂O₂-mediated effects.