The role of pituitary melanocortin receptor 3 (MC3) in regulation of hormone output

Abstract

Introduction/Aim: Of the five melanocortin receptors (MCs: MC1-5) identified to date, the focus of neuroendocrine studies has principally been on MC3 and MC4 due to their role in regulating body weight: a role presumed to be mediated by hypothalamic actions in response to melanocyte stimulating hormone (MSH). Recently, MC3 has been shown to have roles in regulating both statural growth and the timing of puberty: possibly mediated by MC3 expression identified in arcuate growth hormone releasing hormone (GHRH) and kisspeptin neurones, respectively (1). It has long been known that MC3 is expressed in the anterior pituitary and may mediate paracrine interactions within the gland (2). It was the aim of this series of studies to determine the potential impact of mouse pituitary MC3 on physiology: specifically the role of MC3 in pituitary gland function, the pattern of expression of the receptor and potential modifications of function by expression of interacting proteins. Methods/Results: We have determined the impact of loss of MC3 expression on anterior pituitary function using MC3 knockout mice: in adult male mice loss of MC3 leads to a significant reduction in the pituitary content of growth hormone (GH), gonadotrophins and prolactin, with no effect on adrenocorticotrophic hormone (ACTH) or thyroid stimulating hormone; in adult females the reduction is restricted to GH, however, a trend of decrease in gonadotrophins was also found. RNAScope in situ hybridisation showed that MC3 is co-expressed in a large proportion of somatotrophs and gonadotrophs and, consistent with this, imaging showed that ACTH stimulates a rise in intracellular calcium in these cell types. We have also studied the interaction of melanocortin receptor accessory proteins (MRAPs) and found that MRAP2 modifies MC3 response to ACTH but not MSH and results in bias G-protein coupled signalling. RNAScope for MRAP2 revealed that it is co-expressed in a significant proportion of MC3 positive cells. Conclusions: The effects of global knockout of MC3 on pituitary hormone contents suggest that aspects of the body weight, growth and pubertal timing roles of the receptor may also be mediated by its pituitary expression. Furthermore, the interactions of MC3 and MRAPs with the growth hormone secretagogue receptor (3) would be consistent with a pituitary role in growth hormone regulation. (1) Lam et al. (2021) Nature 599:436-441. (2) Roudbaraki et al. (1999) Endocrinol. 140:4874-4885. (3) Rediger et al. (2011) J Biol Chem. 286:39623-31