Extracellular NAD+ regulates intracellular calcium levels and induces activation of human granulocytes.
Beta-NAD+e (extracellular beta-NAD+), present at nanomolar levels in human plasma, has been implicated in the regulation of [Ca2+]i (the intracellular calcium concentration) in various cell types, including blood cells, by means of different mechanisms. Here, we demonstrate that micromolar NAD+e (both the alpha and the beta extracellular NAD+ forms) induces a sustained [Ca2+]i increase in human granulocytes by triggering the following cascade of causally related events: (i) activation of adenylate cyclase and overproduction of cAMP; (ii) activation of protein kinase A; (iii) stimulation of ADP-ribosyl cyclase activity and consequent overproduction of cADP-ribose, a universal Ca2+ mobilizer; and (iv) influx of extracellular Ca2+. The NAD+e-triggered [Ca2+]i elevation translates into granulocyte activation, i.e. superoxide and nitric oxide generation, and enhanced chemotaxis in response to 0.1-10 microM NAD+e. Thus extracellular beta-NAD+e behaves as a novel pro-inflammatory cytokine, stimulating human granulocytes and potentially recruiting them at sites of inflammation.
Bruzzone
Santina
S
Department of Experimental Medicine, Section of Biochemistry, and Center of Excellence for Biomedical Research, University of Genova, Viale Benedetto XV/1, 16132 Genova, Italy.
Moreschi
Iliana
I
Guida
Lucrezia
L
Usai
Cesare
C
Zocchi
Elena
E
De Flora
Antonio
A
D036541:ADP-ribosyl Cyclase / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D002633:Chemotaxis / Q000187:drug effects; D036563:Cyclic ADP-Ribose / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D006098:Granulocytes / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D006801:Humans; D009243:NAD / Q000378:metabolism / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism; D016897:Respiratory Burst; D015398:Signal Transduction; D013481:Superoxides / Q000378:metabolism
D009243:NAD; D013481:Superoxides; D036563:Cyclic ADP-Ribose; D009569:Nitric Oxide; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D036541:ADP-ribosyl Cyclase; D002118:Calcium