Paracrine ADP Ribosyl Cyclase-Mediated Regulation of Biological Processes

Cells. 2022 Aug 24;11(17):2637. doi: 10.3390/cells11172637.

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.

Keywords: CD38; NAD+; connexin 43; cyclic ADP-ribose.

Publication types

  • Review
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADP-ribosyl Cyclase / metabolism
  • ADP-ribosyl Cyclase 1 / metabolism
  • Animals
  • Antigens, CD / metabolism
  • Biological Phenomena*
  • Connexin 43 / metabolism
  • Cyclic ADP-Ribose* / metabolism
  • Mammals / metabolism
  • Membrane Glycoproteins / metabolism
  • NAD / metabolism

Substances

  • Antigens, CD
  • Connexin 43
  • Membrane Glycoproteins
  • NAD
  • Cyclic ADP-Ribose
  • ADP-ribosyl Cyclase
  • ADP-ribosyl Cyclase 1

Grants and funding

This research was funded by the University of Genova and by the Italian Ministry of Education, University and Research (PRIN 2017Z5LR5Z_003).