2-chloroadenosine stimulates granule exocytosis from mouse natural killer cells: evidence for signal transduction through a novel extracellular receptor.
The effect of 2-chloroadenosine (2CA), an adenosine receptor agonist, on the activation status of mouse natural killer (NK) cells was determined. Splenic lymphocytes incubated with 2CA exocytosed an NK cell-associated granzyme with N alpha-CBZ-L-lysine thiobenzyl ester (BLT) esterase activity in a dose- and time-dependent manner. Selective depletion of NK cells by anti-asialoGM1 antibody plus complement pretreatment confirmed that NK cells were the source of the BLT esterase activity. 2CA-induced granule exocytosis was not reduced in the presence of the nucleoside uptake blockers NBTI, dilazep, or dipyridamole, indicating the involvement of an extracellular receptor. However, adenosine or other A1, A2, or A3 cell-surface adenosine receptor agonists failed to trigger the exocytotic process. Furthermore, the nonselective adenosine receptor antagonist theophylline, as well as the selective A1 receptor antagonist DPCPX and the selective A2 receptor antagonist DMPX, did not interfere with 2CA-induced BLT esterase secretion. These data suggest that 2CA acts on NK cells via a novel (non-A1/A2/A3) cell-surface receptor. Genistein, a protein tyrosine kinase inhibitor, and calphostin C, a protein kinase C inhibitor, both interfered with 2CA-induced granule exocytosis. Pertussis toxin, an ADP-ribosylating toxin to which certain GTP-binding proteins are sensitive, also inhibited 2CA-stimulated BLT esterase release. In addition, 2CA-induced granule exocytosis was reduced in the presence of cyclosporin A, an inhibitor of Ca(2+)-dependent signaling pathways, and the Ca(2+)-chelating agent EGTA. We conclude that 2CA, acting through a novel extracellular receptor on mouse NK cells, triggers granule exocytosis via a Ca(2+)-dependent signal transduction pathway that is coupled to GTP-binding proteins and involves protein tyrosine kinase and protein kinase C activation.[1]References
- 2-chloroadenosine stimulates granule exocytosis from mouse natural killer cells: evidence for signal transduction through a novel extracellular receptor. Williams, B.A., Blay, J., Hoskin, D.W. Exp. Cell Res. (1997) [Pubmed]
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