ADP-ribose gating of the calcium-permeable LTRPC2 channel revealed by Nudix motif homology

Free ADP-ribose (ADPR), a product of NAD hydrolysis and a breakdown product of the calcium-release second messenger cyclic ADPR (cADPR), has no define d role as an intracellular signalling molecule in vertebrate systems. Here we show that a 350-amino-acid protein (designated NUDT9) and a homologous d omain (NUDT9 homology domain) near the carboxy terminus of the LTRPC2/TrpC7 putative cation channel(1) both function as specific ADPR pyrophosphatases . Whole-cell and single-channel analysis of HEK-293 cells expressing LTRPC2 show that LTRPC2 functions as a calcium-permeable cation channel that is s pecifically gated by free ADPR. The expression of native LTRPC2 transcripts is detectable in many tissues including the U937 monocyte cell line, in wh ich ADPR induces large cation currents (designated I-ADPR) that closely mat ch those mediated by recombinant LTRPC2. These results indicate that intrac ellular ADPR regulates calcium entry into cells that express LTRPC2.