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- Title
Paracrine ADP Ribosyl Cyclase-Mediated Regulation of Biological Processes.
- Authors
Astigiano, Cecilia; Benzi, Andrea; Laugieri, Maria Elena; Piacente, Francesco; Sturla, Laura; Guida, Lucrezia; Bruzzone, Santina; De Flora, Antonio
- Abstract
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.
- Subjects
NUCLEOSIDE transport proteins; MEMBRANE proteins; IMMUNE checkpoint proteins; CONNEXIN 43; CD38 antigen; NIACIN; RYANODINE
- Publication
Cells (2073-4409), 2022, Vol 11, Issue 17, p2637
- ISSN
2073-4409
- Publication type
Article
- DOI
10.3390/cells11172637