Identification of Cyclic ADP-ribose-dependent Mechanisms in Pancreatic Muscarinic Ca2+ Signaling Using CD38 Knockout Mice

Fukushi, Yasuo; Kato, Ichiro; Takasawa, Shin; Sasaki, Tsukasa; Ong, Boon Hooi; Sato, Mika; Ohsaga, Atsushi; Satô, Kôzô; Shirato, Kunio; Okamoto, Hiroshi; Maruyama, Yoshio

doi:10.1074/jbc.m004469200

Cited by 87 publications

(56 citation statements)

References 39 publications

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“…Multiple defects have been seen in the knock-out mice, indicating the important roles of CD38 in regulating physiological functions (23)(24)(25)(26)(27). In addition to its cADPR-synthesizing activity, CD38 is in fact the only characterized enzyme that can effectively degrade cADPR.…”

Section: Cyclic Adp-ribose (Cadpr)mentioning

confidence: 99%

Catalysis-associated Conformational Changes Revealed by Human CD38 Complexed with a Non-hydrolyzable Substrate Analog

Liu

Kriksunov

Moreau

et al. 2007

Journal of Biological Chemistry

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Cyclic ADP-ribose (cADPR) is a calcium mobilization messenger important for mediating a wide range of physiological functions. The endogenous levels of cADPR in mammalian tissues are primarily controlled by CD38, a multifunctional enzyme capable of both synthesizing and hydrolyzing cADPR. In this study, a novel non-hydrolyzable analog of cADPR, N1-cIDPR (N1-cyclic inosine diphosphate ribose), was utilized to elucidate the structural determinants involved in the hydrolysis of cADPR. N1-cIDPR inhibits CD38-catalyzed cADPR hydrolysis with an IC 50 of 0.26 mM. N1-cIDPR forms a complex with CD38 or its inactive mutant in which the catalytic residue Glu-226 is mutated. Both complexes have been determined by x-ray crystallography at 1.7 and 1.76 Å resolution, respectively. The results show that N1-cIDPR forms two hydrogen bonds (2.61 and 2.64 Å ) with Glu-226, confirming our previously proposed model for cADPR catalysis. Structural analyses reveal that both the enzyme and substrate cADPR undergo catalysis-associated conformational changes. From the enzyme side, residues Glu-146, Asp-147, and Trp-125 work collaboratively to facilitate the formation of the Michaelis complex. From the substrate side, cADPR is found to change its conformation to fit into the active site until it reaches the catalytic residue. The binary CD38-cADPR model described here represents the most detailed description of the CD38-catalyzed hydrolysis of cADPR at atomic resolution. Our structural model should provide insights into the design of effective cADPR analogs. Cyclic ADP-ribose (cADPR)3 is a novel cyclic nucleotide derived from NAD. It is metabolized by a family of proteins called ADP-ribosyl cyclases (1, 2). This cyclic nucleotide features a head-to-tail type of glycosidic linkage (N1-C1Ј) between N1 of its adenine and the anomeric carbon (C1Ј) of the terminal ribose (3, 4). Results obtained in the past decade have established the second messenger role of cADPR in mobilizing calcium stores in various cell types (reviewed in Refs. 5, 6). Its calcium signaling function has since been found to be more versatile and has additionally been shown to modulate calcium influx across the plasma membrane (7, 8) as well as regulate calcium homeostasis within the nucleus (9, 10).Human CD38 is a type II transmembrane glycoprotein containing a small N-terminal tail, a single transmembrane helix, and a large extra-membranous portion that possesses ADPribosyl cyclase activity. As a member of the cyclase family, CD38 not only can synthesize cADPR from NAD but also can hydrolyze NAD and cADPR to produce ADP-ribose (2,(11)(12)(13)(14). At acidic conditions, CD38 can also catalyze the formation and hydrolysis of NAADP, another calcium mobilization messenger (15,16). Although the mechanism of how these various activities of CD38 are regulated inside cells remains to be determined, we have previously identified residue Glu-146 as being critically important for controlling the relative synthesizing and hydrolyzing activities (16,17). The enzymatic portion of human ...

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Section: Cyclic Adp-ribose (Cadpr)mentioning

confidence: 99%

Catalysis-associated Conformational Changes Revealed by Human CD38 Complexed with a Non-hydrolyzable Substrate Analog

Liu

Kriksunov

Moreau

et al. 2007

Journal of Biological Chemistry

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“…Ϫ/Ϫ cells from various tissues (3,47,48), suggesting the possible compensation by other members of the CD38 family (e.g., CD157) or other enzymes capable of generating cADPR or NAADP. Since calcium signals generated by insulin were completely dependent on NAADP (11), our current results suggest that additional NAADP-generating enzymes may be involved in insulin signaling.…”

Section: Tially Inhibited In Cd38mentioning

confidence: 99%

Suppressed Insulin Signaling and Increased Apoptosis inCd38-Null Islets

et al. 2006

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؊/؊ islets were significantly more susceptible to apoptosis compared with islets isolated from littermate controls. This finding correlated with disrupted islet architecture and reduced ␤-cell mass in Cd38 ؊/؊ mice, both in the context of a normal lab diet and a high-fat diet. Nevertheless, we did not find robust differences in glucose homeostasis in vivo or glucose signaling in vitro in Cd38 ؊/؊ mice on the C57BL/6 genetic background, in contrast to previous studies by others of Cd38 knockout mice on the ICR background. Thus, our results suggest that CD38 plays a role in novel antiapoptotic signaling pathways but does not directly control glucose signaling in pancreatic ␤-cells.

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“…Like the acinar cells, the ␤-cells possess ADPribosyl cyclase, which is responsible for the production of both cADPR and NAADP (33,34,74). Therefore, it is likely that NAADP, which has such an important role in the acinar cells, is also physiologically important in the ␤-cells (Fig.…”

Section: Control Of Ca 2؉ Release Channel Sensitivitymentioning

confidence: 99%

Regulation of Intracellular Ca2+ Stores by Multiple Ca2+-Releasing Messengers

Cancela

Petersen

2002

Diabetes

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Identification of Cyclic ADP-ribose-dependent Mechanisms in Pancreatic Muscarinic Ca2+ Signaling Using CD38 Knockout Mice

Abstract: We showed that muscarinic acetylcholine (ACh)-stimulation increased the cellular content of cADPR in the pancreatic acinar cells from normal mice but not in those from CD38 knockout mice.

Cited by 87 publications

References 39 publications

Catalysis-associated Conformational Changes Revealed by Human CD38 Complexed with a Non-hydrolyzable Substrate Analog

Catalysis-associated Conformational Changes Revealed by Human CD38 Complexed with a Non-hydrolyzable Substrate Analog

Suppressed Insulin Signaling and Increased Apoptosis inCd38-Null Islets

Regulation of Intracellular Ca2+ Stores by Multiple Ca2+-Releasing Messengers

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