Localization of the cyclic ADP-ribose-dependent calcium signaling pathway in hepatocyte nucleus

CD38 is a type II transmembrane glycoprotein found on both hematopoietic an d non-hematopoietic cells. It is known for its involvement in the metabolis m of cyclic ADP-ribose (cADPR) and nicotinic acid adenine dinucleotide phos phate, two nucleotides with calcium mobilizing activity independent of inos itol trisphosphate. It is generally believed that CD38 is an integral prote in with ectoenzymatic activities found mainly on the plasma membrane. Here we show that enzymatically active CD38 is present intracellularly on the nu clear envelope of rat hepatocytes. CD38 isolated from rat liver nuclei poss essed both ADP-ribosyl cyclase and NADase activity. Immunofluorescence stud ies on rat liver cryosections and isolated nuclei localized CD38 to the nuc lear envelope of hepatocytes. Subcellular localization via immunoelectron m icroscopy showed that CD38 is located on the inner nuclear envelope. The is olated nuclei sequestered calcium in an ATP-dependent manner. cADPR elicite d a rapid calcium release from the loaded nuclei, which was independent of inositol trisphosphate and was inhibited by 8-amino-cADPR, a specific antag onist of cADPR, and ryanodine. However, nicotinic acid adenine dinucleotide phosphate failed to elicit any calcium release from the nuclear calcium st ores. The nuclear localization of CD38 shown in this study suggests a novel role of CD38 in intracellular calcium signaling for non-hematopoietic cell s.