Ghrelin is produced by and directly activates corticotrope cells from adrenocorticotropin-secreting adenomas.
BACKGROUND
In Cushing's disease, ACTH hypersecretion by pituitary corticotrope adenoma cells and resulting hypercortisolism is accompanied by a severely blunted GH secretory response. Interestingly, in Cushing's disease, ghrelin markedly increases plasma ACTH, whereas its stimulatory action on GH secretion is reduced. Although the reported expression of ghrelin receptors (GHS-R) in corticotrope tumors offers a potential mechanism for ghrelin-induced ACTH hypersecretion, studies on the direct effects of synthetic GH secretagogues on corticotropinoma cells offered contradictory results.


OBJECTIVE
To evaluate the direct action of ghrelin on corticotropinoma cells from two patients with Cushing's disease, we measured its effect on free cytosolic calcium concentration ([Ca(2+)](i)). Additionally, expression of GHS-R and its ligand ghrelin was examined in these cells and in five additional corticotropinomas.


RESULTS
Ghrelin (10(-6) m) induced a marked [Ca(2+)](i) increase in 89.5% (case 1; n = 19 cells) and 85% (case 2; n = 13 cells) of corticotropinoma cells. Moreover, RT-PCR showed that expression of GHS-R isoforms is accompanied by that of ghrelin in all seven corticotrope adenomas examined. Importantly, double immunogold electron microscopy revealed that ghrelin is costored within ACTH secretory vesicles in densely granulated adenomatous corticotropes.


CONCLUSIONS
These results constitute the first demonstration that ghrelin acts directly on corticotrope tumor cells derived from patients with Cushing's disease. The presence of ghrelin and GHS-R suggests that pituitary ghrelin may play an autocrine/paracrine role in regulating ACTH release in Cushing's disease. Our findings provide a plausible cellular basis for the exaggerated ACTH response to ghrelin in Cushing's disease and suggest novel research strategies to develop medical treatments for this disease.
Martínez-Fuentes
Antonio J
AJ
Department of Cell Biology, Physiology, and Immunology, Edificio Severo Ochoa, Planta 3, Campus de Rabanales, University of Córdoba, E-14014 Córdoba, Spain. justo@uco.es.
Moreno-Fernández
Jesús
J
Vázquez-Martínez
Rafael
R
Durán-Prado
Mario
M
de la Riva
Andrés
A
Tena-Sempere
Manuel
M
Diéguez
Carlos
C
Jiménez-Reina
Luis
L
Webb
Susan M
SM
Pumar
Alfonso
A
Leal-Cerro
Alfonso
A
Benito-López
Pedro
P
Malagón
María M
MM
Castaño
Justo P
JP
D000236:Adenoma / Q000378:metabolism*; D000324:Adrenocorticotropic Hormone / Q000378:metabolism*; D000328:Adult; D002118:Calcium / Q000378:metabolism; D005260:Female; D005455:Fluorescent Antibody Technique; D054439:Ghrelin; D006801:Humans; D007150:Immunohistochemistry; D036361:Peptide Hormones / Q000502:physiology*; D010911:Pituitary Neoplasms / Q000378:metabolism*; D011333:Pro-Opiomelanocortin / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D043562:Receptors, G-Protein-Coupled / Q000235:genetics; D054440:Receptors, Ghrelin
D054439:Ghrelin; D036361:Peptide Hormones; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; D054440:Receptors, Ghrelin; D011333:Pro-Opiomelanocortin; D000324:Adrenocorticotropic Hormone; D002118:Calcium