On the accumulation of adenosine 3':5'-monophosphate in Ehrlich cells and adenylate cyclase desensitization in response to epinephrine.

The time course of the action of epinephrine on cAMP levels in isolated mouse Ehrlich ascites cells was studied. Following the addition of hormone (10(-7) to 10(-4) M), cAMP levels reached a maximum within 1 min and declined to about 2 fold basal levels within 10-20 min. The decline phase was not due to the metabolism of epinephrine or accumulation of an inhibitor in the medium. Experiments involving timed additions of theophylline to epinephrine-treated cells suggested that the rate of cAMP synthesis declined progressively with time. Cells treated with epinephrine and then washed free of hormone were shown to be refractory to hormonal stimulation of cAMP levels. Adenylate cyclase prepared from epinephrine-treated cells was shown to exhibit decreased sensitivity to the hormone in in vitro incubations. Resensitization of the enzyme could be achieved by washing pretreated cells free of epinephrine and reincubating them for 1/2 to 2 h. Neither desensitization nor resensitization were prevented by cycloheximide or actinomycin D. Desensitization could not be induced by incubating cels with dibutyryl-cAMP. The desensitization phenomenon is considered to be a mechanism whereby cells protect themselves against the possible harmful effects of high levels of cAMP maintained over a long period of time.