Ectopic beta-adrenergic receptors coupled to adenylate cyclase in human adrenocortical carcinomas.
The adenylate cyclase of an adrenocortical carcinoma of the rat is activated not only by ACTH but also by beta-adrenergic agonists, which bind to ectopic beta-adrenergic receptors not present in normal rat adrenal cortex. Previous reports examining possible beta-adrenergic control of adenylate cyclase in human adrenocortical carcinomas failed to demonstrate beta-adrenergic receptor-linked enzyme activity. We studied six human adrenal carcinomas and normal adrenal cortex from three subjects for beta-adrenergic agonist-sensitive adenylate cyclase and beta-adrenergic binding sites. Three of the six carcinomas had adenylate cyclase responses to both ACTH and beta-agonists. Two tumors were ACTH responsive but not beta-agonist responsive; one tumor responded to beta-agonists but not to ACTH. Adenylate cyclase activity of normal adrenal cortex from three subjects was stimulated by ACTH but not by beta-agonists. In membrane preparations from three tumors with beta-agonist-sensitive adenylate cyclase, the radiolabeled beta-adrenergic antagonist [125I]pindolol bound specifically and with high affinity (Kd = 38-83 pM) to a single class of binding sites which showed saturation with ligand concentration, reversibility of binding, pharmacological specificity, and stereospecificity. Normal cortex and one tumor without beta-adrenergic agonist-sensitive adenylate cyclase had no specific binding of [125I]pindolol. These results indicate that malignant transformation of adrenal cortex in man is frequently but not invariably associated with the appearance of ectopic beta-adrenergic receptors functionally linked to adenylate cyclase. Loss of ACTH-responsive adenylate cyclase may also occur simultaneously with the development of beta-adrenergic receptor-linked adenylate cyclase.
Katz
M S
MS
Kelly
T M
TM
Dax
E M
EM
Pineyro
M A
MA
Partilla
J S
JS
Gregerman
R I
RI
D000262:Adenylyl Cyclases / Q000378:metabolism*; D000302:Adrenal Cortex / Q000201:enzymology; D000310:Adrenal Gland Neoplasms / Q000201:enzymology / Q000378:metabolism*; D000324:Adrenocorticotropic Hormone / Q000494:pharmacology; D000328:Adult; D000368:Aged; D001667:Binding, Competitive; D004837:Epinephrine / Q000494:pharmacology; D005260:Female; D006801:Humans; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009638:Norepinephrine / Q000494:pharmacology; D010869:Pindolol / Q000378:metabolism; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*
D011943:Receptors, Adrenergic, beta; D000324:Adrenocorticotropic Hormone; D010869:Pindolol; D000262:Adenylyl Cyclases; D007545:Isoproterenol; D009638:Norepinephrine; D004837:Epinephrine