Refractoriness of the cyclic AMP response to adenosine and prostaglandin E1 in thymic lymphocytes. Dependence on protein synthesis and energy-providing substrates

Rat thymic lymphocytes exposed to the cyclic AMP-elevating agent, adenosine, become refractory to a subsequent adenosine stimulation. This refractoriness appears distinct from types of refractoriness observed in other tissues. Here induction of refractoriness is not dependent on a prior adenosine stimulus per se but rather on the utilization of the ribose moiety as an energy source. Early addition of other energy-providing substrates, glucose or pyruvate, instead of adenosine also induces refractoriness to adenosine. These circumstances suggest that in this instance, the metabolic state of the cell rather than the presence of a prior stimulus may be the most important determinant. A refractoriness to the cyclic AMP-elevating action of prostaglandin E/sub 1/ also develops without a prior exposure to the stimulus. However, in this case, refractoriness develops rapidly even when no energy source is provided. The data indicate that for both adenosine and PGE/sub 1/, refractoriness is not the result of an accumulation of feedback inhibitors nor, at least for PGE/sub 1/ of a desensitization of adenylate cyclase. In both cases, the development of refractoriness is arrested by inhibiting protein synthesis with either cycloheximide or emetine. While under appropriate conditions, the onset of refractoriness may be fairly rapid, it does notmore » reverse as quickly; the addition of cycloheximide to partially refractory cells leads to only a slight restoration of responsiveness within 2 h. Although some other observations suggest that protein synthesis-dependent refractoriness may be a widespread phenomenon, at least in lymphoid tissues, its physiological meaning is at present poorly understood.« less