Document Detail

Paracrine roles of NAD+ and cyclic ADP-ribose in increasing intracellular calcium and enhancing cell proliferation of 3T3 fibroblasts.
MedLine Citation:
PMID:  11274199     Owner:  NLM     Status:  MEDLINE    
CD38 is a bifunctional ectoenzyme synthesizing from NAD(+) (ADP-ribosyl cyclase) and degrading (hydrolase) cyclic ADP-ribose (cADPR), a powerful universal calcium mobilizer from intracellular stores. Recently, hexameric connexin 43 (Cx43) hemichannels have been shown to release cytosolic NAD(+) from isolated murine fibroblasts (Bruzzone, S., Guida, L., Zocchi, E., Franco, L. and De Flora, A. (2001) FASEB J. 15, 10-12), making this dinucleotide available to the ectocellular active site of CD38. Here we investigated transwell co-cultures of CD38(+) (transfected) and CD38(-) 3T3 cells in order to establish the role of extracellular NAD(+) and cADPR on [Ca(2+)](i) levels and on proliferation of the CD38(-) target cells. CD38(+), but not CD38(-), feeder cells induced a [Ca(2+)](i) increase in the CD38(-) target cells which was comparable to that observed with extracellular cADPR alone and inhibitable by NAD(+)-glycohydrolase or by the cADPR antagonist 8-NH(2)-cADPR. Addition of recombinant ADP-ribosyl cyclase to the medium of CD38(-) feeders induced sustained [Ca(2+)](i) increases in CD38(-) target cells. Co-culture on CD38(+) feeders enhanced the proliferation of CD38(-) target cells over control values and significantly shortened the S phase of cell cycle. These results demonstrate a paracrine process based on Cx43-mediated release of NAD(+), its CD38-catalyzed conversion to extracellular cADPR, and influx of this nucleotide into responsive cells to increase [Ca(2+)](i) and stimulate cell proliferation.
L Franco; E Zocchi; C Usai; L Guida; S Bruzzone; A Costa; A De Flora
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2001-03-27
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  276     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2001 Jun 
Date Detail:
Created Date:  2001-06-11     Completed Date:  2001-07-19     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  21642-8     Citation Subset:  IM    
G. Gaslini Institute, Largo G. Gaslini 5, 16147 Genova, Italy.
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MeSH Terms
3T3 Cells
ADP-ribosyl Cyclase
Adenosine Diphosphate Ribose / analogs & derivatives,  metabolism*,  pharmacology
Antigens, CD*
Antigens, CD38
Antigens, Differentiation / chemistry,  genetics,  metabolism*
Binding Sites
Calcium / metabolism*
Cell Division / physiology*
Cell Membrane / metabolism
Coculture Techniques
Connexin 43 / genetics,  physiology
Cyclic ADP-Ribose
Cytosol / metabolism
Membrane Glycoproteins
Models, Biological
Multienzyme Complexes / chemistry,  metabolism
NAD / metabolism*
NAD+ Nucleosidase / chemistry,  genetics,  metabolism*
Oligodeoxyribonucleotides, Antisense / pharmacology
Recombinant Proteins / chemistry,  metabolism
Reg. No./Substance:
0/Antigens, CD; 0/Antigens, Differentiation; 0/Connexin 43; 0/Membrane Glycoproteins; 0/Multienzyme Complexes; 0/Oligodeoxyribonucleotides, Antisense; 0/Recombinant Proteins; 119340-53-3/Cyclic ADP-Ribose; 20762-30-5/Adenosine Diphosphate Ribose; 53-84-9/NAD; 7440-70-2/Calcium; EC Cyclase; EC, CD38; EC protein, mouse; EC Nucleosidase

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