Endocrine Abstracts (2004) 7 P79

Is there an ultra-short loop feedback of ACTH on itself?

M Sharma1, AM Nanzer1, DG Morris1, EF Adams2, M Korbonits1 & AB Grossman1


1Department of Endocrinology, St. Bartholomew's and the Royal London School of Medicine and Dentistry, London, UK; 2Pharmaceutical Sciences Research Institute, Aston University, Aston Triangle, Birmingham, UK.


It has been postulated that ACTH might modulate its own secretion by a negative feedback loop and we have recently found that the ACTH receptor (MC2R) is present in both normal and tumorous human corticotrophs. In this study we investigated the expression of the ACTH receptor in mouse and rat pituitary tissue as well as mouse pituitary tumour (AtT20) cells and studied the effect of Synacthen (ACTH [1-24]) on ACTH secretion, cAMP release and cell proliferation in AtT20 cells. MC2R mRNA expression was studied by RT-PCR. The ACTH ELISA assay kit protocol was modified to prevent cross-reaction of endogenously secreted ACTH with Synacthen used for treatment of the cells. cAMP was measured by ELISA. We were unable to show expression of ACTH receptor mRNA in either mouse or rat hypothalamus or pituitary, or in AtT20 cells, whereas mouse adrenal tissue and the Y1 mouse adrenal cell line acted as positive controls in our RT-PCR. In rat pituitary cells CRH had a stimulatory effect on ACTH secretion; Synacthen had no effect on either basal or CRH-stimulated ACTH secretion at 4-24 hour stimulation. In AtT20 cells cAMP levels were increased by CRH treatment (control, 59.9±6.0 fmol/well vs. CRH, 106.4±12.3 fmol/well; P=0.015) and decreased by Synacthen (38.5±4.8; P=0.017) while the combined administration had no significant effect. Our data also showed no change in thymidine incorporation using any of the three treatment options (CRH, ACTH [1-24] or the two in combination) at 24-96 hours. In summary, we were unable to demonstrate any expression of the MC2R in either mouse or rat pituitary tissue or in a mouse corticotroph cell line. This is in contrast with our recent human data where MC2R was found to be expressed in normal pituitary and in some corticotroph adenomas. We speculate that the inhibitory effect of Synacthen on cAMP release could be attributed to the activation of an alternative melanocortin receptor.

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