The Ecto-enzyme CD38 Is a Nicotinic Acid Adenine Dinucleotide Phosphate (NAADP) Synthase That Couples Receptor Activation to Ca2+ Mobilization from Lysosomes in Pancreatic Acinar Cells

Marie-Jo Moutin,Antony Galione,Nathalie Cheviron,Frances E. Lund,Jose-Manuel Cancela,François Cosker,Alexis Menteyne,Michiko Yamasaki

doi:10.1074/jbc.m110.125864

Abstract

Nicotinic acid adenine dinucleotide phosphate (NAADP) is the most potent Ca(2+)-mobilizing intracellular messenger and is linked to a variety of stimuli and cell surface receptors. However, the enzyme responsible for endogenous NAADP synthesis in vivo is unknown, and it has been proposed that another enzyme differing from ADP-ribosyl cyclase family members may exist. The ecto-enzyme CD38, involved in many functions as diverse as cell proliferation and social behavior, represents an important alternative. In pancreatic acinar cells, the hormone cholecystokinin (CCK) stimulates NAADP production evoking Ca(2+) signals by discharging acidic Ca(2+) stores and leading to digestive enzyme secretion. From cells derived from CD38(-/-) mice, we provide the first physiological evidence that CD38 is required for endogenous NAADP generation in response to CCK stimulation. Furthermore, CD38 expression in CD38-deficient pancreatic AR42J cells remodels Ca(2+)-signaling pathways in these cells by restoring Ca(2+) mobilization from lysosomes during CCK-induced Ca(2+) signaling. In agreement with an intracellular site for messenger synthesis, we found that CD38 is expressed in endosomes. These CD38-containing vesicles, likely of endosomal origin, appear to be proximal to lysosomes but not co-localized with them. We propose that CD38 is an NAADP synthase required for coupling receptor activation to NAADP-mediated Ca(2+) release from lysosomal stores in pancreatic acinar cells.

Highlights

Nicotinic acid adenine dinucleotide phosphate (NAADP) is the most potent Ca2؉-mobilizing intracellular messenger and is linked to a variety of stimuli and cell surface receptors
From cells derived from CD38؊/؊ mice, we provide the first physiological evidence that CD38 is required for endogenous NAADP generation in response to CCK stimulation
Increases in NAADP levels have been reported in pancreatic ␤-cells after glucose (15) and glucagon-like peptide-1 stimulation (17), in pancreatic acinar cells after CCK stimulation (16), in pulmonary smooth muscle following exposure to endothelin-1 (3), in response to histamine in human myometrial cells (18), and glutamate in neurones (19)

Summary

Introduction

Nicotinic acid adenine dinucleotide phosphate (NAADP) is the most potent Ca2؉-mobilizing intracellular messenger and is linked to a variety of stimuli and cell surface receptors. All three major Ca2ϩ-mobilizing messengers, IP3, cADPR, and NAADP have been shown to play a role in stimulus-secretion coupling in these cells (27), but in mouse pancreatic acinar cells, the high affinity CCKA receptor, activated by low physiological picomolar CCK concentrations (28), appears to be coupled to NAADP signaling (7, 16, 29, 30) These low concentrations of CCK, like ACh, stimulates cADPR synthesis (16), but IP3 production only is linked to muscarinic and low affinity CCK receptors (28). In agreement with our previous work, our data suggest that CCK may enhance the endocytosis of plasma membrane CD38 into endosomal vesicles, creating an intracellular site for messenger synthesis (4, 33) These results reveal that CD38 is an NAADP synthase in mammalian cells coupling receptor activation to NAADP-dependent Ca2ϩ release from lysosomal stores

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Conclusion