title: Basal CD38/cyclic ADP-ribose-dependent signaling mediates ATP release and survival of microglia by modulating connexin 43 hemichannels.
abstract: It is necessary to investigate the mechanisms underlying ATP release from neural cells, because extracellular ATP plays multiple important biological roles in the brain. CD38 is an ectoenzyme that consumes NAD(+) to produce cyclic ADP-ribose (cADPR), a potent agonist of ryanodine receptors. Our previous study showed that CD38 reductions led to microglial apoptosis. In this study, we used both murine microglial BV2 cells and primary microglial cultures as cellular models to test our hypothesis that basal CD38/cyclic ADP-ribose (CD38/cADPR)-dependent signaling plays a key role in ATP release, which mediates basal survival of microglia. We found that inhibition of CD38/cADPR-dependent signaling by CD38 silencing or 8-Bromo-cADPR, a ryanodine receptor antagonist, produced significant ATP release from BV2 microglia. Cx43 small interfering RNA and Cx43 hemichannel blocker 18-α-glycyrrhetinic acid completely prevented the CD38 silencing or 8-Bromo-cADPR-induced ATP release. Prevention of the ATP release could also be due to P2X7 receptor antagonists. Our study has further suggested a key role of ATP release in the microglial apoptosis induced by decreased CD38/cADPR-dependent signaling. In addition, by using primary microglial cultures, we found that 8-Bromo-cADPR also induced significant ATP release, which could be attenuated by 18-α-glycyrrhetinic acid. 8-Bromo-cADPR was also found to induce death of primary microglial cultures. In conclusion, our results have suggested novel roles of basal activation of CD38/cADPR-dependent signaling in mediating microglial functions and survival: It mediates ATP release from microglia by modulating Cx43 hemichannels, which can significantly affect microglial survival.
authors.affiliation: Med-X Research Institute and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200030, People's Republic of China.
authors.forename: Yingxin
authors.initials: Y
authors.lastname: Ma
authors.forename: Wei
authors.initials: W
authors.lastname: Cao
authors.forename: Lu
authors.initials: L
authors.lastname: Wang
authors.forename: Jingwen
authors.initials: J
authors.lastname: Jiang
authors.forename: Hui
authors.initials: H
authors.lastname: Nie
authors.forename: Ban
authors.initials: B
authors.lastname: Wang
authors.forename: Xunbin
authors.initials: X
authors.lastname: Wei
authors.forename: Weihai
authors.initials: W
authors.lastname: Ying
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000502:physiology*; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000502:physiology; D018031:Connexin 43 / Q000502:physiology*; D008562:Membrane Glycoproteins / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D018031:Connexin 43; D008562:Membrane Glycoproteins; D000255:Adenosine Triphosphate; C498155:Cd38 protein, mouse; D051997:ADP-ribosyl Cyclase 1
keywords: apoptosis; extracellular ATP; microglia function