Glucagon inhibits ACTH-stimulated cortisol secretion from dispersed human adrenocortical cells by activating unidentified receptors negatively coupled with the adenylate cyclase cascade.
We have investigated the direct effect of glucagon on collagenase-dispersed adrenocortical cells obtained from consenting patients undergoing unilateral adrenalectomy and nephrectomy for renal cancer. Dispersed cells, actually a mixture of zona glomerulosa and zona fasciculata-reticularis (ZF/R) cells, were incubated with glucagon (from 10(-10) to 10(-6) M) alone or in the presence of 10(-9) M angiotensin-II, 10(-10) M ACTH or 10(-5) M forskolin, and the effects on aldosterone, cortisol and cyclic-AMP (cAMP) production were measured by radioimmune assay. Glucagon concentration-dependently inhibited ACTH-stimulated cortisol production and ACTH- or forskolin-enhanced cAMP release, minimal and maximal effective concentrations being 10(-9) and 10(-7) M. The effects of glucagon were suppressed by 10(-5) M Des-His1-[Glu9]glucagon amide, an antagonist of glucagon receptors (glucagon-A). Reverse transcription-polymerase chain reaction did not reveal the presence of specific glucagon-receptor mRNA in the human adrenal cortex. However, autoradiography demonstrated the presence of [125I]glucagon binding sites in the ZF/R, which were displaced by glucagon but not by ACTH. Taken together, these findings suggest that glucagon, through the activation of unidentified receptors located on ZF/R cells, inhibits adenylate cyclase, thereby dampening glucocorticoid response to ACTH.
Mazzocchi
G
G
Department of Human Anatomy and Physiology, University of Padua, Italy.
Gottardo
L
L
Aragona
F
F
Albertin
G
G
Nussdorfer
G G
GG
D000262:Adenylyl Cyclases / Q000378:metabolism*; D000302:Adrenal Cortex / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D000324:Adrenocorticotropic Hormone / Q000494:pharmacology*; D000450:Aldosterone / Q000096:biosynthesis; D000804:Angiotensin II / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000096:biosynthesis; D005934:Glucagon / Q000494:pharmacology*; D006801:Humans; D006854:Hydrocortisone / Q000096:biosynthesis / Q000378:metabolism*; D008099:Liver / Q000737:chemistry; D008979:Moloney murine leukemia virus / Q000201:enzymology; D012333:RNA, Messenger / Q000032:analysis; D012194:RNA-Directed DNA Polymerase; D018027:Receptors, Glucagon / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015383:Zona Fasciculata / Q000187:drug effects / Q000378:metabolism; D015384:Zona Glomerulosa / Q000187:drug effects / Q000378:metabolism
D012333:RNA, Messenger; D018027:Receptors, Glucagon; D000804:Angiotensin II; D005576:Colforsin; D000450:Aldosterone; D000324:Adrenocorticotropic Hormone; D005934:Glucagon; D000242:Cyclic AMP; D012194:RNA-Directed DNA Polymerase; D000262:Adenylyl Cyclases; D006854:Hydrocortisone