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

Murray, J.F., Berruien, N., Dowejko, M.M., Santiago Andres, Y, Laiho, L, Andoniadou, C, Fiordelisio, T, Le Tissier, P. and Smith, C.L. 2022. The role of pituitary melanocortin receptor 3 (MC3) in regulation of hormone output. The International Congress of Neuroendocrinology. SEC, Glasgow, Scotland, UK 07 - 10 Aug 2022

TitleThe role of pituitary melanocortin receptor 3 (MC3) in regulation of hormone output
AuthorsMurray, J.F., Berruien, N., Dowejko, M.M., Santiago Andres, Y, Laiho, L, Andoniadou, C, Fiordelisio, T, Le Tissier, P. and Smith, C.L.
TypeConference poster
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.

KeywordsMelanocortin, MRAP, Pituitary,
Year2022
ConferenceThe International Congress of Neuroendocrinology
Publication dates
PublishedAug 2022
Web address (URL) of conference proceedingshttps://confpartners.eventsair.com/QuickEventWebsitePortal/icn22/icn2022/Agenda/AgendaItemDetail?id=55465410-e421-44fd-bb5a-ef37cfee4e13

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Smith, C.L., Anthony, S., Malaki, M., Hubank, M., Leiper, J.M. and Vallance, P. 2005. Pathophysiological concentrations of ADMA alter human coronary artery endothelial cell gene expression: an insight into the pathophysiological significance of raised plasma ADMA levels. in: Boger, R., Fleming, I. and Waltenberger, J. (ed.) Vascular Biology and Medicine: 3rd European Meeting, Hamburg, September 2005, abstracts Germany Karger.

Potential therapeutic benefit of novel DDAH inhibitors for the treatment of endotoxemia
Nandi, M., Rossiter, S., Torondel, B., Malaki, M., Smith, C.L., Stidwill, R., Leiper, J.M. and Vallance, P. 2005. Potential therapeutic benefit of novel DDAH inhibitors for the treatment of endotoxemia. in: Boger, R., Fleming, I. and Waltenberger, J. (ed.) Vascular Biology and Medicine: 3rd European Meeting, Hamburg, September 2005, abstracts Germany Karger.

Evidence of systemic and pulmonary endothelial dysfunction in the Dimethylarginine Dimethylaminohydrolase I (DDAH I+/-) heterozygous knockout mouse
Malaki, M., Nandi, M., Madhani, M., Gill, H., Smith, C.L., Leiper, J.M. and Vallance, P. 2005. Evidence of systemic and pulmonary endothelial dysfunction in the Dimethylarginine Dimethylaminohydrolase I (DDAH I+/-) heterozygous knockout mouse. in: Boger, R., Fleming, I. and Waltenberger, J. (ed.) Vascular Biology and Medicine: 3rd European Meeting, Hamburg, September 2005, abstracts Germany Karger.

Dimethylarginine dimethylaminohydrolase I (DDAH I) heterozygous knockout mice display a cardiovascular phenotype consisting of pulmonary and systemic endothelial dysfunction
Malaki, M., Nandi, M., Madhani, M., Gill, H., Smith, C.L., Leiper, J.M. and Vallance, P. 2005. Dimethylarginine dimethylaminohydrolase I (DDAH I) heterozygous knockout mice display a cardiovascular phenotype consisting of pulmonary and systemic endothelial dysfunction. British Pharmaceutical Society Summer Meeting. Cambridge, UK 06-08 Jul 2005

Leptin expression in the fetus and placenta during mouse pregnancy
Malik, N.M., Carter, N.D., Wilson, C.A., Scaramuzzi, R.J., Stock, M.J. and Murray, J.F. 2005. Leptin expression in the fetus and placenta during mouse pregnancy. Placenta. 26 (1), pp. 47-52. https://doi.org/10.1016/j.placenta.2004.03.009

Cardiovascular tests: use & limits of biochemical markers - therapeutic measurements of ADMA involved in cardiovascular disorders
Smith, C.L. and Vallance, P. 2005. Cardiovascular tests: use & limits of biochemical markers - therapeutic measurements of ADMA involved in cardiovascular disorders. Current Pharmaceutical Design. 11 (17), pp. 2177-2185. https://doi.org/10.2174/1381612054367364

Selective substrate-based inhibitors of mammalian dimethylarginine dimethylaminohydrolase
Rossiter, S., Smith, C.L., Malaki, M., Nandi, M., Gill, H., Leiper, J.M., Vallance, P. and Selwood, D.L. 2005. Selective substrate-based inhibitors of mammalian dimethylarginine dimethylaminohydrolase. Journal of Medicinal Chemistry. 48 (14), pp. 1670-1678. https://doi.org/10.1021/jm050187a

Effects of ADMA upon gene expression: an insight into the pathophysiological significance of raised plasma ADMA
Smith, C.L., Anthony, S., Hubank, M., Leiper, J.M. and Vallance, P. 2005. Effects of ADMA upon gene expression: an insight into the pathophysiological significance of raised plasma ADMA. PLoS Medicine. 2 (10), pp. 1031-1043. https://doi.org/10.1371/journal.pmed.0020264

Effects of low dose ADMA on gene expression in human coronary artery endothelial cells
Smith, C.L., Leiper, J.M. and Vallance, P. 2004. Effects of low dose ADMA on gene expression in human coronary artery endothelial cells. Nitric Oxide: Biology and Chemistry. 11 (1), p. 59. https://doi.org/10.1016/j.niox.2004.07.003

Restoration of nitric oxide production by N-hydroxy-L-arginine in endothelial cells with NO deficiency triggered by elevated glucose
Crabtree, M.J., Smith, C.L. and Gross, S.S. 2004. Restoration of nitric oxide production by N-hydroxy-L-arginine in endothelial cells with NO deficiency triggered by elevated glucose. Nitric Oxide: Biology and Chemistry. 11 (1), p. 65. https://doi.org/10.1016/j.niox.2004.07.003

Overexpression of dimethylarginine dimethylaminohydrolase enhances tumour hypoxia: an insight into the relationship of hypoxia and angiogenesis In vivo
Kostourou, V., Troy, H., Murray, J.F., Cullis, E.R., Whitley, G.S.J., Griffiths, J.R. and Robinson, S. 2004. Overexpression of dimethylarginine dimethylaminohydrolase enhances tumour hypoxia: an insight into the relationship of hypoxia and angiogenesis In vivo. NeoPlasia. 6 (4), pp. 401-411. https://doi.org/10.1593/neo.04109

Effects of low dose ADMA on gene expression in human coronary artery endothelial cells
Smith, C.L., Leiper, J.M. and Vallance, P. 2004. Effects of low dose ADMA on gene expression in human coronary artery endothelial cells. 3rd International Conference on the Biology, Chemistry and Therapeutic Applications of Nitric Oxide: 4th Anuual Scientific Meeting of the Nitric Oxide Society of Japan. Nara, Japan 24-28 May 2004

Restoration of nitric oxide production by N-hydroxyarginine in endothelial cells with NO deficiency triggered by elevated glucose
Crabtree, M.J., Smith, C.L. and Gross, S.S. 2004. Restoration of nitric oxide production by N-hydroxyarginine in endothelial cells with NO deficiency triggered by elevated glucose. 3rd International Conference on the Biology, Chemistry and Therapeutic Applications of Nitric Oxide: 4th Anuual Scientific Meeting of the Nitric Oxide Society of Japan. Nara, Japan 24-28 May 2004

Neonatal 5HT activity antagonizes the masculinizing effect of testosterone on the luteinizing hormone release response to gonadal steroids and on brain structures in rats
Murray, J.F., Dakin, C.L., Siddiqui, A., Pellatt, L.J., Ahmed, S., Ormerod, L.J.A., Swan, A.V., Davies, D.C. and Wilson, C.A. 2004. Neonatal 5HT activity antagonizes the masculinizing effect of testosterone on the luteinizing hormone release response to gonadal steroids and on brain structures in rats. European Journal of Neuroscience. 19 (2), pp. 387-395. https://doi.org/10.1111/j.0953-816X.2003.03158.x

Central orexin A has site-specific effects on luteinizing hormone release in female rats
Small, C.J., Goubillon, M.L., Murray, J.F., Siddiqui, A., Grimshaw, S.E., Young, H., Sivanesan, V., Kalamatianos, T., Kennedy, A.R., Coen, C.W., Bloom, S.R. and Wilson, C.A. 2003. Central orexin A has site-specific effects on luteinizing hormone release in female rats. Endocrinology. 144 (7), pp. 3225-3236. https://doi.org/10.1210/en.2002-0041

Measurement of cardiac troponin I in striated muscle using three experimental methods
Fredericks, S., Bainbridge, K., Murray, J.F., Collinson, P.O., Carter, N.D. and Holt, D.W. 2003. Measurement of cardiac troponin I in striated muscle using three experimental methods. Annals of Clinical Biochemistry. 40 (3), pp. 244-248. https://doi.org/10.1258/000456303321610547

Dimethylarginine dimethylaminohydrolase activity modulates ADMA levels, VEGF expression, and cell phenotype
Smith, C.L., Birdsey, G.M., Anthony, S., Arrigoni, F.I., Leiper, J.M. and Vallance, P. 2003. Dimethylarginine dimethylaminohydrolase activity modulates ADMA levels, VEGF expression, and cell phenotype. Biochemical and Biophysical Research Communications. 308 (4), pp. 984-989. https://doi.org/10.1016/S0006-291X(03)01507-9

Cardiac troponin T and creatine kinase MB content in skeletal muscle of the uremic rat
Fredericks, S., Murray, J.F., Carter, N.D., Chesser, A.M.S., Papachristou, S., Yaqoob, M.M., Collinson, P.O., Gaze, D. and Holt, D.W. 2002. Cardiac troponin T and creatine kinase MB content in skeletal muscle of the uremic rat. Clinical Chemistry. 48 (6), pp. 859-868.

The redox status of bound pterin cofactor determines whether eNOS produces NO or superoxide anion: [3H] - BH4 binding studies provide insights into vascular pathophysiology
Jones, C.L., Vasquez-Vivar, J., Kalyanaraman, B., Griscavage-Ennis, J.M., Gross, S.S. and Smith, C.L. 2002. The redox status of bound pterin cofactor determines whether eNOS produces NO or superoxide anion: [3H] - BH4 binding studies provide insights into vascular pathophysiology. in: Milstien, S., Kapatos, G., Levine, R.A. and Shane, B. (ed.) Chemistry and biology of pteridines and folates: proceedings of the 12th International Symposium on Pteridines and Folates, National Institutes of Health, Bethesda, M.D. Boston, USA Kluwer Academic Publishers. pp. 271-276

Activation and inactivation of neuronal nitric oxide synthase: characterization of Ca2+-dependent [125I]Calmodulin binding
Weissman, B.A., Jones, C.L., Liu, Q., Gross, S.S. and Smith, C.L. 2002. Activation and inactivation of neuronal nitric oxide synthase: characterization of Ca2+-dependent [125I]Calmodulin binding. European Journal of Pharmacology. 435 (1), pp. 9-18. https://doi.org/10.1016/S0014-2999(01)01560-6

Leptin requirement for conception, implantation, and gestation in the mouse
Malik, N.M., Carter, N.D., Murray, J.F., Scaramuzzi, R.J., Wilson, C.A. and Stock, M.J. 2001. Leptin requirement for conception, implantation, and gestation in the mouse. Endocrinology. 142 (12), pp. 5198-5202.

Cardiac troponin T and creatine kinase MB are not increased in exterior oblique muscle of patients with renal failure
Fredericks, S., Murray, J.F., Bewick, M., Chang, R., Collinson, P.O., Carter, N.D. and Holt, D.W. 2001. Cardiac troponin T and creatine kinase MB are not increased in exterior oblique muscle of patients with renal failure. Clinical Chemistry. 47 (6), pp. 1023-1030.

Chapter 10: Tetrahydrobiopterin: An Essential Cofactor of Nitric Oxide Synthase with an Elusive Role
Smith, C.L. 2000. Chapter 10: Tetrahydrobiopterin: An Essential Cofactor of Nitric Oxide Synthase with an Elusive Role. in: Ignarro, L.J. (ed.) Nitric Oxide: Biology and Pathobiology Elsevier. pp. 167-185

Carbon monoxide induces vasodilation and nitric oxide release but suppresses endothelial NOS
Thorup, C., Jones, C.L., Gross, S.S., Moore, L.C. and Goligorsky, M.S. 1999. Carbon monoxide induces vasodilation and nitric oxide release but suppresses endothelial NOS. American journal of physiology. 277 (6), pp. F882-F889.

An autoinhibitory control element defines calcium-regulated isoforms of nitric oxide synthase
Salerno, J.C., Harris, D.E., Irizarry, K., Patel, B., Morales, A.J., Smith, S.M.E., Martasek, P., Roman, L.J., Masters, B.S.S., Jones, C.L., Weissman, B.A., Lane, P., Liu, Q., Gross, S.S. and Smith, C.L. 1997. An autoinhibitory control element defines calcium-regulated isoforms of nitric oxide synthase. Journal of Biological Chemistry. 272 (47), pp. 29769-29777.

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