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V Ramkumar, ME Olah, KA Jacobson and GL Stiles
Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710.
Desensitization of adenosine receptors (ARs) was studied in DDT1 MF-2 cells, which possess both A1- and A2AR, differentially coupled to adenylate cyclase. (-)-N6-(R)-Phenylisopropyladenosine (R-PIA), an A1AR- selective agonist at the appropriate concentrations, desensitized A1AR- mediated inhibition of adenylate cyclase activity in a time- (t1/2, 8 hr) and dose-dependent and reversible fashion. This was associated with significant decreases in total A1AR number and in the number of receptors possessing a high affinity for agonist in membrane preparations. The decrease in total A1AR in the membranes from the desensitized cells (approximately 40%) was associated with a 37% increase in A1AR measured in light vesicle preparations, compared with control cells. To test a possible role of phosphorylation in A1AR desensitization, cells were incubated with [32P]orthophosphate, followed by exposure to R-PIA for 18 hr. Subsequent purification of the A1AR indicated a 3-4-fold increase in phosphorylation of A1AR in cells treated with R-PIA, compared with control cells. Desensitization of the A1AR did not alter the levels of alpha s and alpha 12 proteins or affect the ability of stimulatory effectors, such as isoproterenol, sodium fluoride, and forskolin, to activate adenylate cyclase. These results suggest that uncoupling, down-regulation, and phosphorylation of the A1AR contribute, at least in part, to desensitization of this inhibitory receptor. Desensitization of the A2AR was characterized using an A2-selective agonist, 2-[4-(2-(4- aminophenyl]methylcarbonyl)ethyl)phenyl]ethylamino- 5'-N- ethylcarboxamidoadenosine (PAPA-APEC). Pretreatment of cells with PAPA- APEC (100 nM) resulted in a rapid loss of agonist stimulation of adenylate cyclase activity (t1/2 of this effect, 45 min). This effect was dose dependent (EC50, approximately 10 nM) and rapidly reversible. Interestingly, desensitization of the A2AR resulted in no change in receptor number, affinity, or mobility on sodium dodecyl sulfate- polyacrylamide gel electrophoresis. Taken together, these data suggest distinct mechanisms of desensitization of A1- and A2ARs in a single cell type.
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