Ramanjaneya, Manjunath, Conner, Alex C., Chen, J. (Jing), Stanfield, Peter R. and Randeva, Harpal S.. (2008) Orexins stimulate steroidogenic acute regulatory protein expression through multiple signaling pathways in human adrenal H295R cells. Endocrinology, Volume 149 (Number 8). pp. 4106-4115. ISSN 0013-7227

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Abstract

Orexins mediate a variety of physiological processes, including feeding behavior, the circadian pathway, and cortisol secretion. Steroidogenesis is regulated by a variety of neuropeptides, and one of the key rate-limiting steps is cholesterol transport across the mitochondrial membrane by the steroidogenic acute regulatory protein (StAR). StAR expression can be regulated through several different signaling pathways. Despite the clear link between orexins and steroid production, the actions of the orexin family of hormones on steroid biosynthesis are not fully understood. We present data showing that 100 nM of both orexins A and B for 4 or 24 h significantly up-regulates StAR, in H295R pluripotent adrenocortical cells. We present the dose-dependent and time-dependent characteristics of StAR up-regulation at the protein level, showing significant increases after 4 h at a relatively low agonist concentration (1 nM). We have provided a key analysis of the precise G protein-coupled signaling pathways required for the up-regulation of StAR in response to orexins A and B. This has involved dominant-negative G protein analysis, and the direct inhibition of the protein kinase A, protein kinase C, ERK1/2, and p38 pathways. This shows a fundamental role for multiple G protein-coupled and MAPK-mediated signaling pathways leading to StAR expression. Antagonist analysis also showed that orexin effects on StAR were primarily, but not exclusively, acting through the orexin receptor type 1. This is the first study linking orexin action on StAR expression and comprehensively describes the signaling pathways involved in regulating the complexity of hormone biosynthesis.

Item Type:	Journal Article
Subjects:	Q Science > QP Physiology R Medicine > RC Internal medicine
Divisions:	Faculty of Medicine > Warwick Medical School > Metabolic and Vascular Health Faculty of Medicine > Warwick Medical School
Library of Congress Subject Headings (LCSH):	Orexins -- Physiological effect, Adrenal glands
Journal or Publication Title:	Endocrinology
Publisher:	The Endocrine Society
ISSN:	0013-7227
Date:	August 2008
Volume:	Volume 149
Number:	Number 8
Number of Pages:	10
Page Range:	pp. 4106-4115
Identification Number:	10.1210/en.2007-1739
Status:	Peer Reviewed
Publication Status:	Published
Access rights to Published version:	Restricted or Subscription Access
Funder:	General Charities of the City of Coventry, British Heart Foundation
Grant number:	PG/03/131/16192 (BHF)
References:	1. Sakurai T, Amemiya A, Ishii M, Matsuzaki I, Chemelli RM, Tanaka H, Williams SC, Richarson JA, Kozlowski GP, Wilson S, Arch JR, Buckingham RE, Haynes AC, Carr SA, Annan RS, McNulty DE, Liu WS, Terrett JA, Elshourbagy NA, Bergsma DJ, Yanagisawa M 1998 Orexins and orexin re- ceptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 92:697 2. Holmqvist T, Johansson L, Ostman M, Ammoun S, Akerman KE, Kukkonen JP 2005 OX1 orexin receptors couple to adenylyl cyclase regulation via multiple mechanisms. J Biol Chem 280:6570–6579 3. Karteris E, Randeva HS 2003 Orexin receptors and G-protein coupling: evidence for another “promiscuous” seven transmembrane domain receptor. J Pharmacol Sci 93:126–128 4. Ammoun S, Holmqvist T, Shariatmadari R, Oonk HB, Detheux M, Parmentier M, Akerman KE, Kukkonen JP 2003 Distinct recognition of OX1 and OX2 receptors by orexin peptides. J Pharmacol Exp Ther 305:507–514 5. Karteris E, Randeva HS, Grammatopoulos DK, Jaffe RB, Hillhouse EW 2001 Expression and coupling characteristics of theCRHand orexin type 2 receptors in human fetal adrenals. J Clin Endocrinol Metab 86:4512–4519 6. Randeva HS, Karteris E, Grammatopoulos D, Hillhouse EW 2001 Expression of orexin-A and functional orexin type 2 receptors in the human adult adrenals: implications for adrenal function and energy homeostasis. J Clin Endocrinol Metab 86:4808–4813 7. Johren O, Bruggemann N, Dominiak P 2004 Orexins (hypocretins) and adrenal function. Horm Metab Res 36:370–375 8. Perello M, Moreno G, Gaillard RC, Spinedi E 2004 Glucocorticoid-dependency of increased adiposity in a model of hypothalamic obesity. Neuro Endocrinol Lett 25:119–126 9. Ziolkowska A, Spinazzi R, Albertin G, Nowak M, Malendowicz LK, Tortorella C, NussdorferGG2005 Orexins stimulate glucocorticoid secretion from cultured rat and human adrenocortical cells, exclusively acting via the OX1 receptor. J Steroid Biochem Mol Biol 96:423–429 10. Spinazzi R, Rucinski M, Neri G, Malendowicz LK, Nussdorfer GG 2005 Preproorexin and orexin receptors are expressed in cortisol-secreting adrenocortical adenomas, and orexins stimulate in vitro cortisol secretion and growth of tumor cells. J Clin Endocrinol Metab 90:3544–3549 11. Goodfriend TL, Egan BM, Kelley DE 1998 Aldosterone in obesity. Endocr Res 24:789–796 12. Lamounier-Zepter V, Bornstein SR, Ehrhart-Bornstein M 2004 Mechanisms of obesity-related hypertension. Horm Metab Res 36:376–380 13. Miller WL 2007 Steroidogenic acute regulatory protein (StAR), a novel mitochondrial cholesterol transporter. Biochim Biophys Acta 1771:663–676 14. New MI 2003 Inborn errors of adrenal steroidogenesis. Mol Cell Endocrinol 211:75–83 15. Clark BJ, Wells J, King SR, Stocco DM 1994 The purification, cloning, and expression of a novel luteinizing hormone-induced mitochondrial protein in MA-10 mouse Leydig tumor cells. Characterization of the steroidogenic acute regulatory protein (StAR). J Biol Chem 269:28314–28322 16. Stocco DM 2001 Tracking the role of a star in the sky of the new millennium. Mol Endocrinol 15:1245–1254 17. Lin D, Sugawara T, Strauss 3rd JF, Clark BJ, Stocco DM, Saenger P, Rogol A, Miller WL 1995 Role of steroidogenic acute regulatory protein in adrenal and gonadal steroidogenesis. Science 267:1828–1831 18. Le Roy C, Li JY, Stocco DM, Langlois D, Saez JM 2000 Regulation by adrenocorticotropin (ACTH), angiotensin II, transforming growth factor-�, and insulin-like growth factor I of bovine adrenal cell steroidogenic capacity and expression of ACTH receptor, steroidogenic acute regulatory protein, cytochrome P450c17, and 3�-hydroxysteroid dehydrogenase. Endocrinology 141: 1599–1607 19. Reinhart AJ, Williams SC, Stocco DM 1999 Transcriptional regulation of the StAR gene. Mol Cell Endocrinol 151:161–169 20. Stocco DM, Wang X, Jo Y, Manna PR 2005 Multiple signaling pathways regulating steroidogenesis and steroidogenic acute regulatory protein expression: more complicated than we thought. Mol Endocrinol 19:2647–2659 21. Rainey WE, Bird IM, Mason JI 1994 The NCI-H295 cell line: a pluripotent model for human adrenocortical studies. Mol Cell Endocrinol 100:45–50 22. Pfaffl MW, Lange IG, Daxenberger A, Meyer HH 2001 Tissue-specific expression pattern of estrogen receptors (ER): quantification of ER� and ER� mRNA with real-time RT-PCR. APMIS 109:345–355 23. Manna PR, Stocco DM 2005 Regulation of the steroidogenic acute regulatory protein expression: functional and physiological consequences. Curr Drug Targets Immune Endocr Metabol Disord 5:93–108 24. Roberts PJ, Der CJ 2007 Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer. Oncogene 26:3291–3310 25. Smart D, Sabido-David C, Brough SJ, Jewitt F, Johns A, Porter RA, Jerman JC 2001 SB-334867-A: the first selective orexin-1 receptor antagonist. Br J Pharmacol 132:1179–1182 26. Malendowicz LK, Tortorella C, Nussdorfer GG 1999 Orexins stimulate corticosterone secretion of rat adrenocortical cells, through the activation of the adenylate cyclase-dependent signaling cascade. J Steroid Biochem Mol Biol 70:185–188 27. Mazzocchi G, Malendowicz LK, Gottardo L, Aragona F, NussdorferGG2001 Orexin A stimulates cortisol secretion from human adrenocortical cells through activation of the adenylate cyclase-dependent signaling cascade. J Clin Endocrinol Metab 86:778–782 28. Magga J, Bart G, Oker-Blom C, Kukkonen JP, Akerman KE, Nasman J 2006 Agonist potency differentiates G protein activation and Ca2�signalling by the orexin receptor type 1. Biochem Pharmacol 71:827–836 29. Simpson ER, WatermanMR1988 Regulation of the synthesis of steroidogenic enzymes in adrenal cortical cells by ACTH. Annu Rev Physiol 50:427–440 30. Hammer F, Stewart PM 2006 Cortisol metabolism in hypertension. Best Pract Res Clin Endocrinol Metab 20:337–353 31. Miller WL 1998 Early steps in androgen biosynthesis: from cholesterol to DHEA. Baillieres Clin Endocrinol Metab 12:67–81 32. Stocco DM, Clark BJ 1996 Role of the steroidogenic acute regulatory protein (StAR) in steroidogenesis. Biochem Pharmacol 51:197–205 33. Hilairet S, Bouaboula M, Carriere D, Le Fur G, Casellas P 2003 Hypersensitization of the Orexin 1 receptor by the CB1 receptor: evidence for cross-talk blocked by the specific CB1 antagonist, SR141716. J Biol Chem 278:23731–23737 34. Manna PR, Chandrala SP, Jo Y, StoccoDM2006 cAMP-independent signaling regulates steroidogenesis in mouse Leydig cells in the absence of StAR phosphorylation. J Mol Endocrinol 37:81–95 35. Betancourt-Calle S, Calle RA, Isales CM, White S, Rasmussen H, Bollag WB 2001 Differential effects of agonists of aldosterone secretion on steroidogenic acute regulatory phosphorylation. Mol Cell Endocrinol 173:87–94 36. Clark BJ, Pezzi V, Stocco DM, Rainey WE 1995 The steroidogenic acute regulatory protein is induced by angiotensin II and K� in H295R adrenocortical cells. Mol Cell Endocrinol 115:215–219 37. Lopez M, Senaris R, Gallego R, Garcia-Caballero T, Lago F, Seoane L, Casanueva F, Dieguez C 1999 Orexin receptors are expressed in the adrenal medulla of the rat. Endocrinology 140:5991–5994 38. Catt KJ, Carson MC, Hausdorff WP, Leach-Harper CM, Baukal AJ, Guillemette G, Balla T, AguileraG1987 Angiotensin II receptors and mechanisms of action in adrenal glomerulosa cells. J Steroid Biochem 27:915–927 39. Fleury A, Mathieu AP, Ducharme L, Hales DB, LeHoux JG 2004 Phosphorylation and function of the hamster adrenal steroidogenic acute regulatory protein (StAR). J Steroid Biochem Mol Biol 91:259–271 40. Martinelle N, Holst M, Soder O, Svechnikov K 2004 Extracellular signalregulated kinases are involved in the acute activation of steroidogenesis in immature rat Leydig cells by human chorionic gonadotropin. Endocrinology 145:4629–4634 41. Krug AW, Vleugels K, Schinner S, Lamounier-Zepter V, Ziegler CG, Bornstein SR, Ehrhart-Bornstein M 2007 Human adipocytes induce an ERK1/2 MAP kinases-mediated upregulation of steroidogenic acute regulatory protein (StAR) and an angiotensin II-sensitization in human adrenocortical cells. Int J Obes (Lond) 31:1605–1616 42. Foster RH 2004 Reciprocal influences between the signalling pathways regulating proliferation and steroidogenesis in adrenal glomerulosa cells. J Mol Endocrinol 32:893–902 43. Otis M, Gallo-Payet N 2007 Role of MAPKs in angiotensin II-induced steroidogenesis in rat glomerulosa cells. Mol Cell Endocrinol 265- 266:126–130 44. Svechnikov K, Stocco DM, Soder O 2003 Interleukin-1� stimulates steroidogenic acute regulatory protein expression via p38 MAP kinase in immature rat Leydig cells. J Mol Endocrinol 30:59–67 45. Manna PR, Chandrala SP, King SR, Jo Y, Counis R, Huhtaniemi IT, Stocco DM 2006 Molecular mechanisms of insulin-like growth factor-I mediated regulation of the steroidogenic acute regulatory protein in mouse Leydig cells. Mol Endocrinol 20:362–378 46. Martinat N, Crepieux P, Reiter E, Guillou F 2005 Extracellular signal-regulated kinases (ERK) 1, 2 are required for luteinizing hormone (LH)-induced steroidogenesis in primary Leydig cells and control steroidogenic acute regulatory (StAR) expression. Reprod Nutr Dev 45:101–108
URI:	http://wrap.warwick.ac.uk/id/eprint/29680

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