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The transmembrane glycoprotein CD38 is a catalytically active transporter responsible for generation and influx of the second messenger cyclic ADP‐ribose across membranes

CD38 is a type II transmembrane glycoprotein expressed in many vertebrate cells. It is a bifunctional ectoenzyme that catalyzes both the synthesis of Cyclic ADP‐ribose (cADPR) from NAD+ and the degradation of cADPR to ADP‐ribose by means of its ADP‐ribosyl cyclase and cADPR‐hydrolase activities, respectively. The cyclase also converts NGD+ to cyclic GDP‐ribose (cGDPR), which is refractory to cADPR‐hydrolase. cADPR, but not cGDPR, is a potent calcium mobilizer from intracellular stores. It has been demonstrated to be a new second messenger involved in the regulation of calcium homeostasis in many cell types, from plants to mammals. The number of physiological processes shown to be regulated by cADPR is steadily increasing. A topological paradox exists because ectocellularly generated cADPR acts intracellularly. Here we demonstrate that the catalytic functioning of CD38 is accompanied by a cADPR (cGDPR) ‐transporting activity across natural and artificial membranes. In resealed membranes from CD38+ human erythrocytes, transport of catalytically generated cADPR or cGDPR was saturation dependent and occurred against a concentration gradient. Likewise, CD38‐reconstituted proteoliposomes were active in concentrating NAD+ (NGD+) ‐derived cADPR (cGDPR) inside the vesicle compartment. Moreover, the cADPR‐transporting activity in CD38 proteoliposomes prevented the hydrolase‐catalyzed degradation to ADPR that occurs conversely with detergent‐solubilized CD38, resulting in selective influx of cADPR. In the CD38 proteoliposomes, catalytically active CD38 exhibited monomeric, dimeric, and tetrameric structures. In CD38 sense‐ but not in antisense‐transfected HeLa cells, externally added NAD+ resulted in significant, transient increases in cytosolic calcium. These data suggest that transmembrane juxtaposition of two or four CD38 monomers can generate a catalytically active channel for selective formation and influx of cADPR (cGDPR) to reach cADPR‐responsive intracellular calcium stores.—Franco, L., Guida, L., Bruzzone, S., Zocchi, E., Usai, C., De Flora, A. The transmembrane glycoprotein CD38 is a catalytically active transporter responsible for generation and influx of the second messenger cyclic ADP‐ribose across membranes. FASEB J. 12, 1507–1520 (1998)