A novel site of action of a high affinity A1 adenosine receptor antagonist
Ramkumar, V.; Stiles, G.L.
Biochemical and Biophysical Research Communications 153(3): 939-944
1988
ISSN/ISBN: 0006-291X PMID: 3134023 Document Number: 306567
XAC, a high affinity antagonist of the A1 adenosine receptor, enhances adenylate cyclase activity by 1.3-2 fold with an EC50 of .apprx. 47 nM in adipocyte membranes pretreated with adenosine deaminase to eliminate adenosine and in the presence of total phosphodiesterase inhibition by 100 .mu.M papaverine. This effect of XAC is observed only at concentrations of GTP sufficient to activate Gi (.apprx. 5 .times. 10-6 M GTP) and is not evident in the absence or presence of lower GTP concentrations. ADP ribosylation of Gi by pertussis toxin treatment also abolishes this stimulatory action of XAC. Furthermore, in the presence of GTP activation of inhibitory prostaglandin E1 receptors diminishes the stimulatory effect of XAC on adenylate cyclase. In addition, XAC interferes with GTP-mediated inhibition of forskolin-stimulated adenylate cyclase activity in a noncompetitve manner. Finally, XAC is only a weak inhibitor of the low Km cyclic AMP phosphodiesterase, producing .apprx.40% inhibition of phosphodiesterase activity at a concentration of 100 .mu.M. These data suggest that XAC increases adenylate cyclase activity in absence of endogenous adenosine by inhibiting tonic Gi activity in a reversible manner.