Epinephrine or prostaglandin E1 pretreatment of intact S-49 lymphoma cells specifically desensitized adenylate cyclase activity. Cholate extracts of membranes from these desensitized cells showed no difference from controls in their reconstitution of hormone-stimulated adenylate cyclase activity in the adenylate cyclase-deficient variant (cyc-) of the lymphoma cell line. Adenylate cyclase in the cyc- variant was also specifically desensitized by epinephrine in prostaglandin E1. The desensitization was assessed by reconstituting the cyc- adenylate cyclase with cholate extracts of the wild type lymphoma cells. Since the cyc- has been shown to lack the coupling or G/F proteins of the adenylate cyclase complex, and these proteins are restored by cholate extracts from wild type cells, we conclude that the G/F proteins are not altered or necessary for specific desensitization of the lymphoma cell lines.