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Paracrine ADP Ribosyl Cyclase-Mediated Regulation of Biological Processes

期刊

CELLS
卷 11, 期 17, 页码 -

出版社

MDPI
DOI: 10.3390/cells11172637

关键词

CD38; connexin 43; NAD(+); cyclic ADP-ribose

资金

  1. University of Genova
  2. Italian Ministry of Education, University and Research [PRIN 2017Z5LR5Z_003]

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ADP-ribosyl cyclases (ADPRCs) catalyze the synthesis of the Ca2+-active second messengers Cyclic ADP-ribose (cADPR) and ADP-ribose (ADPR) from NAD(+) as well as nicotinic acid adenine dinucleotide phosphate (NAADP(+)) from NADP(+). CD38 is the best characterized ADPRC in mammals, with two opposite membrane orientations: type II and type III. Type II CD38 is a glycosylated ectoenzyme, while type III CD38 has its active site in the cytosol.
ADP-ribosyl cyclases (ADPRCs) catalyze the synthesis of the Ca2+-active second messengers Cyclic ADP-ribose (cADPR) and ADP-ribose (ADPR) from NAD(+) as well as nicotinic acid adenine dinucleotide phosphate (NAADP(+)) from NADP(+). The best characterized ADPRC in mammals is CD38, a single-pass transmembrane protein with two opposite membrane orientations. The first identified form, type II CD38, is a glycosylated ectoenzyme, while type III CD38 has its active site in the cytosol. The ectoenzymatic nature of type II CD38 raised long ago the question of a topological paradox concerning the access of the intracellular NAD(+) substrate to the extracellular active site and of extracellular cADPR product to its intracellular receptors, ryanodine (RyR) channels. Two different transporters, equilibrative connexin 43 (Cx43) hemichannels for NAD(+) and concentrative nucleoside transporters (CNTs) for cADPR, proved to mediate cell-autonomous trafficking of both nucleotides. Here, we discussed how type II CD38, Cx43 and CNTs also play a role in mediating several paracrine processes where an ADPRC(+) cell supplies a neighboring CNT-and RyR-expressing cell with cADPR. Recently, type II CD38 was shown to start an ectoenzymatic sequence of reactions from NAD(+)/ADPR to the strong immunosuppressant adenosine; this paracrine effect represents a major mechanism of acquired resistance of several tumors to immune checkpoint therapy.

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