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Nicotinic acid adenine dinucleotide phosphate (NAADP) and cyclic ADP-ribose (cADPR) are Ca(2+)-mobilizing messengers important for modulating cardiac excitation-contraction coupling and pathophysiology. CD38, which belongs to the ADP-ribosyl cyclase family, catalyzes synthesis of both NAADP and cADPR in vitro However, it remains unclear whether this is the main enzyme for their production under physiological conditions. Here we show that membrane fractions from WT but not CD38(-/-) mouse hearts supported NAADP and cADPR synthesis. Membrane permeabilization of cardiac myocytes with saponin and/or Triton X-100 increased NAADP synthesis, indicating that intracellular CD38 contributes to NAADP production. The permeabilization also permitted immunostaining of CD38, with a striated pattern in WT myocytes, whereas CD38(-/-) myocytes and nonpermeabilized WT myocytes showed little or no staining, without striation. A component of β-adrenoreceptor signaling in the heart involves NAADP and lysosomes. Accordingly, in the presence of isoproterenol, Ca(2+) transients and contraction amplitudes were smaller in CD38(-/-) myocytes than in the WT. In addition, suppressing lysosomal function with bafilomycin A1 reduced the isoproterenol-induced increase in Ca(2+) transients in cardiac myocytes from WT but not CD38(-/-) mice. Whole hearts isolated from CD38(-/-) mice and exposed to isoproterenol showed reduced arrhythmias. SAN4825, an ADP-ribosyl cyclase inhibitor that reduces cADPR and NAADP synthesis in mouse membrane fractions, was shown to bind to CD38 in docking simulations and reduced the isoproterenol-induced arrhythmias in WT hearts. These observations support generation of NAADP and cADPR by intracellular CD38, which contributes to effects of β-adrenoreceptor stimulation to increase both Ca(2+) transients and the tendency to disturb heart rhythm.

Original publication

DOI

10.1074/jbc.M117.789347

Type

Journal article

Journal

J Biol Chem

Publication Date

11/08/2017

Volume

292

Pages

13243 - 13257

Keywords

CD38, Ca2+, cardiac arrhythmia, cardiac hypertrophy, cyclic ADP-ribose (cADPR), heart, lysosomes, nicotinic acid adenine dinucleotide phosphate (NAADP), sarcoplasmic reticulum (SR), β-adrenoceptor, Adrenergic beta-Agonists, Animals, Anti-Arrhythmia Agents, Antigens, CD38, Calcium Signaling, Cell Membrane Permeability, Cells, Cultured, Cyclic ADP-Ribose, Detergents, Enzyme Inhibitors, Heart, In Vitro Techniques, Male, Membrane Glycoproteins, Mice, Inbred C57BL, Mice, Knockout, Molecular Docking Simulation, Myocardial Contraction, Myocytes, Cardiac, NADP, Protein Transport, Rabbits, Sarcoplasmic Reticulum, Single-Cell Analysis