NAADP mobilizes Ca²⁺ from a thapsigargin-sensitive store in the nuclear envelope by activating ryanodine receptors

Ca²⁺ release from the envelope of isolated pancreatic acinar nuclei could be activated by nicotinic acid adenine dinucleotide phosphate (NAADP) as well as by inositol 1,4,5-trisphosphate (IP₃) and cyclic ADP-ribose (cADPR). Each of these agents reduced the Ca²⁺ concentration inside the nuclear envelope, and this was associated with a transient rise in the nucleoplasmic Ca²⁺ concentration. NAADP released Ca²⁺ from the same thapsigargin-sensitive pool as IP₃. The NAADP action was specific because, for example, nicotineamide adenine dinucleotide phosphate was ineffective. The Ca²⁺ release was unaffected by procedures interfering with acidic organelles (bafilomycin, brefeldin, and nigericin). Ryanodine blocked the Ca²⁺-releasing effects of NAADP, cADPR, and caffeine, but not IP₃. Ruthenium red also blocked the NAADP-elicited Ca²⁺ release. IP₃ receptor blockade did not inhibit the Ca²⁺ release elicited by NAADP or cADPR. The nuclear envelope contains ryanodine and IP₃ receptors that can be activated separately and independently; the ryanodine receptors by either NAADP or cADPR, and the IP₃ receptors by IP₃.