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A novel mechanism for coupling cellular intermediary metabolism to cytosolic Ca²⁺ signaling via CD38/ADP-ribosyl cyclase, a putative intracellular NAD⁺ sensor

LI SUN¹, OLUGBENGA A. ADEBANJO¹, ANATOLIY KOVAL¹, HINDUPUR K. ANANDATHEERTHAVARADA^*,1, JAMEEL IQBAL, XING Y. WU, BALJIT S. MOONGA, XUE B. WU, GOPA BISWAS^*, PETER J. R. BEVIS, MASAYOSHI KUMEGAWA, SOLOMON EPSTEIN, CHRISTOPHER L.-H. HUANG, NARAYAN G. AVADHANI^*, ETSUKO ABE and MONE ZAIDI²

Mount Sinai Bone Program, Departments of Medicine and Geriatrics, and Bronx Veterans Affairs Geriatrics Research Education and Clinical Center (GRECC), New York, New York 10029, USA;
^* School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA;
Physiological Laboratory, Cambridge, UK; and
University of Meikai, Saitama, Japan

²Correspondence: Division of Endocrinology, PO 1055, Annenberg 5, Mount Sinai School of Medicine, One Gustave Levy Place, New York NY 10029, USA. E-mail: mone.zaidi{at}mssm.edu

CD38 is an ectocyclase that converts NAD⁺ to the Ca²⁺-releasing second messenger cyclic ADP-ribose (cADPr). Here we report that in addition to CD38 ecto-catalysis, intracellularly expressed CD38 may catalyze NAD⁺cADPr conversion to cause cytosolic Ca²⁺ release. High levels of CD38 were found in the plasma membranes, endoplasmic reticulum, and nuclear membranes of osteoblastic MC3T3-E1 cells. More important, intracellular CD38 was colocalized with target ryanodine receptors. The cyclase also converted a NAD⁺ surrogate, NGD⁺, to its fluorescent product, cGDPr (K_m 5.13 µM). NAD⁺ also triggered a cytosolic Ca²⁺ signal. Similar results were obtained with NIH3T3 cells, which overexpressed a CD38-EGFP fusion protein. The ^-49-CD38-EGFP mutant with a deleted amino-terminal tail and transmembrane domain appeared mainly in the mitochondria with an expected loss of its membrane localization, but the NAD⁺-induced cytosolic Ca²⁺ signal was preserved. Likewise, Ca²⁺ release persisted in cells transfected with the Myr-^-49-CD38-EGFP or ^-49-CD38-EGFP-Fan mutants, both directed to the plasma membrane but in an opposite topology to the full-length CD38-EGFP. Finally, ryanodine inhibited Ca²⁺ signaling, indicating the downstream activation of ryanodine receptors by cADPr. We conclude that intracellularly expressed CD38 might link cellular NAD⁺ production to cytosolic Ca²⁺ signaling.—Sun, L., Adebanjo, O. A., Koval, A., Anandatheerthavarada, H. K., Iqbal, J., Wu, X. Y., Moonga, B. S., Wu, X. B., Biswas, G., Bevis, P. J. R., Kumegawa, M., Epstein, S., Huang, C. L.-H., Avadhani, N. G., Abe, E., Zaidi, M. A novel mechanism for coupling cellular intermediary metabolism to cytosolic Ca²⁺ signaling via CD38/ADP-ribosyl cyclase, a putative intracellular NAD⁺ sensor.

Key Words: endoplasmic reticulum • ryanodine receptor • myristoylation • osteoblasts

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