With the cloning of the gene encoding pro-opiomelanocortin (POMC) it became apparent that several other peptides distinct from ACTH would be co-secreted from the anterior pituitary into the circulation. This begged the question as to whether these peptides have any biological actions on the adrenal, or to that matter any other tissue. Over the past two decades it has become apparent that the N-terminal fragment known as pro-gamma-MSH plays a role in adrenal physiology.
In humans, pro-gamma-MSH is a 76 residue peptide consisting of a 48 residue N-terminal fragment flanked by a dibasic cleavage site and gamma-MSH at the C-terminal end. Additionally, the N-terminal fragment contains 2 disulphide bridges giving the peptide a 'C' shape.
Previous work has assigned two biological actions to this peptide on the adrenal. Both pro-gamma-MSH and synthetic Lys-gamma-MSH potentiate the steroidogenic actions of ACTH. The mechanism for this involves an increase in free cholesterol within the cell by increasing cholesterol ester hydrolase activity. In contrast, the N-terminal fragment of pro-gamma-MSH, not containing the gamma-MSH sequence, is an adrenal mitogen. This mitogenic activity is not possessed by the full-length peptide, and led to the hypothesis that pro-gamma-MSH is cleaved following secretion from the pituitary. In support of this, we identified a protease necessary for adrenal growth and capable of cleaving the full-length peptide. However, the receptor through which the mitogenic action is mediated is as yet uncharacterised.
Although the MC3 receptor is implicated as the 'gamma-MSH receptor' its high affinity for ACTH and its lack of significant expression in the adrenal strongly suggests that this receptor does not mediate the steroid potentiating effects of gamma-MSH. It is therefore likely that a further MC like receptor exists and this is supported by studies that suggest a number of tissues not expressing the MC3R express high affinity binding sites for gamma-MSH.
03 - 05 Nov 2003
Society for Endocrinology