The pro-opiomelanocortin (POMC)-derived peptides, pro-gamma-MSH and Lys-gamma3-MSH, have been shown to potentiate the steroidogenic action of Adrenocorticotropic hormone (ACTH) on the adrenal cortex. The molecular mechanisms for this potentiation are unclear, but it has been shown that gamma-MSH peptides promote mitochondrial cholesterol accumulation in the adrenal cortex by upregulating the activity of Hormone Sensitive Lipase (HSL) (1). HSL activity is regulated either by upregulation of mRNA levels or by phosphorylation. Using quantitative PCR we were unable to find any increase in HSL mRNA expression in adrenal cells following stimulation with gamma-MSH peptides, suggesting that gamma-MSH peptides regulate the activity of HSL by phosphorylation. Recently the Melanocortin 3 Receptor (MC3-R), the only known receptor to have high affinity for gamma-MSH peptides, has been suggested to be expressed in the adrenal (2). To assess the role that the (MC3-R) plays in mediating the effects of gamma-MSH peptides on the adrenal, the actions of the potent MC3-R agonist MTII and antagonist SHU9119 were analysed using the Lowry perfused adrenal cell column system (3). MTII failed to mimic gamma-MSH mediated potentiation of ACTH-induced steroidogenesis, while SHU9119 did not antagonise the effects of gamma-MSH peptides. In addition, using a signal transduction reporter system, we have found that gamma-MSH peptides do not activate classical melanocortin receptor cyclic-AMP pathway signalling. In contrast, gamma-MSH peptides activate N-FAT and SRE transcription factors, which corroborate with findings that, gamma-MSH peptides induce changes in intracellular free calcium (4). Taken together, these results suggest that gamma-MSH peptides act through a melanocortin receptor distinct from the MC3-R to potentiate the action of ACTH on the adrenal.
(1) Pedersen, R.C. and Brownie, A.C. (1987) Mol Cell Endo 50, 149-156.
(2) Dhillo et al., (2003), Bicohem Biophys Res Commun 301 (1), 102-7.
(3) Lowry, P.J. and McMartin, C. (1974) Biochem J 142, 287-294.
(4) Langouche et al.,(2001) Endocrinology 142, 257-266.
03 - 05 Nov 2003
Society for Endocrinology