Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 280, Issue 4, Pages 2888-2895Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M409592200
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CD38 is an ADP-ribosyl cyclase, producing a potent Ca2+ mobilizer cyclic ADP-ribose (cADPR). In this study, we have investigated a role of CD38 and its regulation through interleukin-8 (IL8) signaling in lymphokine-activated killer (LAK) cells. Incubation of IAK cells with IL8 resulted in an increase of cellular cADPR level and a rapid rise of intracellular Ca2+ concentration ([Ca2+](i)), which was sustained for a long period of time (> 10 min). Preincubation of an antagonistic cADPR analog, 8-Br-cADPR (8-bromo-cyclic adenosine diphosphate ribose), abolished the sustained Ca2+ signal only but not the initial Ca2+ rise. An inositol 1,4,5-trisphosphate (IP3) receptor antagonist blocked both Ca2+ signals. Interestingly, the sustained Ca2+ rise was not observed in the absence of extracellular Ca2+. Functional CD38-null (CD38(-)) LAK cells showed the initial rapid increase of [Ca2+](i) but not the sustained Ca2+ rise in response to IL8 treatment. An increase of cellular cADPR level by cGMP analog, 8-pCPT-cGMP (8-(4-chlorophenylthio)guanosine-3',5'-cyclic monophosphate), but not cAMP analog or phorbol 12-myristate 13-acetate was observed. IL8 treatment resulted in the increase of cGMP level that was inhibited by the IP3 receptor blocker but not a protein kinase C inhibitor. cGMP-mediated Ca2+ rise was blocked by 8-Br-cADPR. In addition, IL8-mediated IAK cell migration was inhibited by 8-Br-cADPR and a protein kinase G inhibitor. Consistent with these observations, IL8-induced migration of CD38(-) IAK cells was not observed. However, direct application of cADPR or 8-pCPT-cGMP stimulated migration of CD38- cells. These results demonstrate that CD38 is stimulated by sequential activation of IL8 receptor, IP3-mediated Ca2+ rise, and cGMP/protein kinase G and that CD38 plays an essential role in IL8-induced migration of LAK cells.
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