G_s and G_i are guanine nucleotide-binding, heterotrimer proteins that regulate the activity of adenylate cyclase, and are responsible for transferring stimulatory and inhibitory hormonal signals, respectively, from cell surface receptors to the enzyme catalytic unit^1–3. These proteins can be directly activated by agents such as GTP and analogues, fluoride and magnesium^2,4,5. Decreased amounts of G_s and G_i and even the absence of G_s, have been described^6–9, whereas an altered G_s has been reported in a cultured cell line (UNC variant of S49 lymphoma cells¹⁰), but has never been observed in human disease states. We have found a profoundly altered G_s protein in a group of human growth hormone-secreting pituitary adenomas, characterized by high secretory activity and intracellular cyclic AMP levels. In the membranes from these tumours no stimulation of adenylate cyclase activity by growth hormone-releasing hormone, by GTP or by fluoride was observed. Indeed, the last two agents caused an inhibition, probably mediated by G_i. In contrast, adenylate cyclase stimulation by Mg²⁺ was enormously increased. This altered pattern of adenylate cyclase regulation was reproduced when a cholate extract of the tumour membranes (which contains G proteins) was reconstituted with G_s-free, cyc⁻ S49 cell membranes. Inasmuch as secretion from somatotrophic cells is known to be a cAMP-dependent function¹¹, the alteration of G_s could be the direct cause of the high secretory activity of the tumours in which it occurs.