A schematic diagram comparing the protein structures of TRP subfamilies. TRP proteins carry six transmembrane segments (S1 to S6). (A, E) TRPC and TRPP subfamilies contain EF hand domain that binds intracellular Ca2+. (A) CIRB is a calmodulin/IP3R-binding domain. (B, E) TRPML and TRPP contain ER retention signlaling domain. (C) NUDIX, named after nucleoside diphosphate-linked moiety-X, is a homologous region in the phosphohydrolase family that binds to ADP ribose. The NUDIX represents a unique activation mechanism, gating by ADP ribose, on TRPM2. Other activators, such as cyclic ADPR and NAD+, as well as inhibitors also target the NUDIX. C-terminal serine/threonine kinase is similar in structure to protein kinase A. (D) TRPV contains ARD and TRP box, similar to TRPC. (F) TRPA1 contains more than 14 ARDs at its N-terminus.