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

• Published in: Nature (London) Vol. 411; no. 6837; pp. 595 - 599
• Main Authors: Scharenberg, Andrew M, Perraud, Anne-Laure, Fleig, Andrea, Dunn, Christopher A, Bagley, Leigh Ann, Launay, Pierre, Schmitz, Carsten, Stokes, Alexander J, Zhu, Qiqin, Bessman, Maurice J, Penner, Reinhold, Kinet, Jean-Pierre
• Format: Journal Article
• Language: English
• Published: London Nature Publishing 31-05-2001; Nature Publishing Group
• Subjects: Adenosine Diphosphate Ribose - metabolism; ADP-ribose; Amino Acid Motifs; Amino Acid Sequence; Amino acids; Animals; Biological and medical sciences; Calcium; Calcium - metabolism; Calcium Channels - chemistry; Calcium Channels - genetics; Calcium Channels - metabolism; Cell Line; Cell membranes. Ionic channels. Membrane pores; Cell structures and functions; Cellular biology; Cloning, Molecular; Escherichia coli; Fundamental and applied biological sciences. Psychology; Humans; Hydrolysis; Ion Channel Gating; Ion Channels - chemistry; Ion Channels - genetics; Ion Channels - metabolism; Ions; Membrane Proteins; Molecular and cellular biology; Molecular Sequence Data; Monosaccharides; Proteins; Pyrophosphatases - chemistry; Pyrophosphatases - genetics; Pyrophosphatases - metabolism; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; Sequence Homology, Amino Acid; Sodium - metabolism; Sugars; Tetracycline; Tetracyclines; TRPC Cation Channels; TRPM Cation Channels; U937 Cells; Vertebrates; Vertebrata; Regulation(control); Calcium ion; Mammalia; ADPribose pyrophosphatase; Enzymatic activity; Enzyme; Hydrolases; Homology; Ionic channel
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/35079100

Free ADP-ribose (ADPR), a product of NAD hydrolysis and a breakdown product of the calcium-release second messenger cyclic ADPR (cADPR), has no defined role as an intracellular signalling molecule in vertebrate systems. Here we show that a 350-amino-acid protein (designated NUDT9) and a homologous domain (NUDT9 homology domain) near the carboxy terminus of the LTRPC2/TrpC7 putative cation channel 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 specifically gated by free ADPR. The expression of native LTRPC2 transcripts is detectable in many tissues including the U937 monocyte cell line, in which ADPR induces large cation currents (designated IADPR) that closely match those mediated by recombinant LTRPC2. These results indicate that intracellular ADPR regulates calcium entry into cells that express LTRPC2.