Melanocortin 2 Receptor-Associated Protein (MRAP) and MRAP2 in Human Adrenocortical Tissues: Regulation of Expression and Association with ACTH Responsiveness

Hofland, Johannes; Delhanty, Patric J. D.; Steenbergen, Jacobie; Hofland, Leo J.; Koetsveld, Peter M. van; Nederveen, Francien H. van; Herder, Wouter W. de; Feelders, Richard A; Jong, Frank H. de

doi:10.1210/jc.2011-2328

Cited by 26 publications

(22 citation statements)

References 38 publications

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“…These data suggest that MC2R and MRAP are important for adrenal gland development, and the adrenal histology of FGD supports this hypothesis as the glands from deceased patients demonstrate disorganisation of glomerulosa cells with almost complete absence of fasciculata and reticularis cells (Clark & Weber 1998). It has also been demonstrated that in vivo, mRNA levels of both MC2R and MRAP in the adrenal gland are regulated by ACTH (Xing et al 2010, Hofland et al 2012. However, at times of acute stress, the immediate steroidogenic response would depend on adequate levels of MRAP and MC2R at the surface and that can be readily trafficked to the plasma membrane.…”

Section: Melanocortin 2 Receptor Accessory Protein and Adrenal Gland mentioning

confidence: 54%

“…Binding of ACTH to MC2R results in increase of cAMP and activation of protein kinase A, which is essential for the expression of steroidogenic enzymes and cortisol production. MC2R appears to be positively regulated by its ligand (Hofland et al 2012), and some studies have suggested a rare involvement of MC2R in adrenal cortisol-secreting tumours (Latronico et al 1995, Arnaldi et al 1998. MC2R is predominantly expressed in all zones of the adrenal cortex, but ACTH mostly acts on the zona fasciculata (Mountjoy et al 1992).…”

Section: Melanocortin 2 Receptor Is a Critical Component Of The Hpa Axismentioning

confidence: 99%

“…However, the role of MRAP/MRAP2 heterodimers remains to be elucidated as one study demonstrated negative regulation of the MRAP/MC2R complex by MRAP2 (Sebag & Hinkle 2010), whereas other studies demonstrated either no effect on the signalling properties of the MC2R/MRAP complex (Gorrigan et al 2011) or that MRAP2 augments MC2R signalling (Agulleiro et al 2010). A study of human adrenocortical tissues demonstrated an association between patient ACTH and cortisol levels and adrenal expression of MRAP and MC2R, but not MRAP2 (Hofland et al 2012). Mutation of the glycosylation site of MRAP2 abolishes MC2R response to ACTH but does not affect facilitation of MC2R surface expression, suggesting that MRAP2 might have two separate accessory roles (Chan et al 2009b).…”

Section: Mrap2 In the Adrenal Glandmentioning

confidence: 99%

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Melanocortin receptor accessory proteins in adrenal gland physiology and beyond

Novoselova

Jackson

Campbell

et al. 2013

Journal of Endocrinology

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The melanocortin receptor (MCR) family consists of five G-protein-coupled receptors (MC1R-MC5R) with diverse physiological roles. MC1R controls pigmentation, MC2R is a critical component of the hypothalamic-pituitary-adrenal axis, MC3R and MC4R have a vital role in energy homeostasis and MC5R is involved in exocrine function. The melanocortin receptor accessory protein (MRAP) and its paralogue MRAP2 are small single-pass transmembrane proteins that have been shown to regulate MCR expression and function. In the adrenal gland, MRAP is an essential accessory factor for the functional expression of the MC2R/ACTH receptor. The importance of MRAP in adrenal gland physiology is demonstrated by the clinical condition familial glucocorticoid deficiency, where inactivating MRAP mutations account for w20% of cases. MRAP is highly expressed in both the zona fasciculata and the undifferentiated zone. Expression in the undifferentiated zone suggests that MRAP could also be important in adrenal cell differentiation and/or maintenance. In contrast, the role of adrenal MRAP2, which is highly expressed in the foetal gland, is unclear. The expression of MRAPs outside the adrenal gland is suggestive of a wider physiological purpose, beyond MC2R-mediated adrenal steroidogenesis. In vitro, MRAPs have been shown to reduce surface expression and signalling of all the other MCRs (MC1,3,4,5R). MRAP2 is predominantly expressed in the hypothalamus, a site that also expresses a high level of MC3R and MC4R. This raises the intriguing possibility of a CNS role for the MRAPs. Hypothalamic-pituitary-adrenal axisThe adrenal glands are responsible for releasing different classes of hormones. The inner part of the glands, the medulla, secretes catecholamines under the control of the sympathetic nervous system. The outer part, the cortex, has three functionally distinct layers -the outer zona glomerulosa that secretes aldosterone, the middle zona fasciculata that produces glucocorticoids and the inner zona reticularis that is responsible for the production of adrenal androgens. Production and release of glucocorticoids by the zona fasciculata are tightly regulated by the hypothalamus and pituitary to control

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Section: Melanocortin 2 Receptor Accessory Protein and Adrenal Gland mentioning

confidence: 54%

Section: Melanocortin 2 Receptor Is a Critical Component Of The Hpa Axismentioning

confidence: 99%

Section: Mrap2 In the Adrenal Glandmentioning

confidence: 99%

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Melanocortin receptor accessory proteins in adrenal gland physiology and beyond

Novoselova

Jackson

Campbell

et al. 2013

Journal of Endocrinology

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“…Samples included normal adrenals obtained at nephrectomy because of renal cell carcinoma and hyperplastic adrenals and excised because of incurable Cushing's disease or ectopic ACTH secretion. Shortly after resection, adrenal tissue samples were dissected and primary single-layer cell cultures prepared as described previously (15). Viable lipid-laden cells were counted after isolation and plated at a density of 100,000 cells/well in DMEM-F-12 containing 5% FCS.…”

Section: Methodsmentioning

confidence: 99%

Protein kinase C-induced activin A switches adrenocortical steroidogenesis to aldosterone by suppressing CYP17A1 expression

Hofland¹,

Steenbergen²,

Hofland³

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

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Functional zonation of the adrenal cortex is a consequence of the zone-specific expression of P450c17 (CYP17A1) and its cofactors. Activin and inhibin peptides are differentially produced within the zones of the adrenal cortex and have been implicated in steroidogenic control. In this study, we investigated whether activin and inhibin can function as intermediates in functional zonation of the human adrenal cortex. Activin A suppressed CYP17A1 expression and P450c17 function in adrenocortical cell lines as well as in primary adrenal cell cultures. Inhibin βA-subunit mRNA and activin A protein levels were found to be increased up to 1,900-fold and 49-fold, respectively, after protein kinase C (PKC) stimulation through PMA or angiotensin II in H295R adrenocortical carcinoma cells. This was confirmed in HAC15 cells and for PMA in primary adrenal cell cultures. Both PMA and Ang II decreased CYP17A1 expression in the adrenocortical cell lines, whereas PMA concurrently suppressed CYP17A1 levels in the primary cultures. Inhibition of activin signaling during PKC stimulation through silencing of the inhibin βA-subunit or blocking of the activin type I receptor opposed the PMA-induced downregulation of CYP17A1 expression and P450c17 function. In contrast, PKA stimulation through adrenocorticotrophin or forskolin increased expression of the inhibin α-subunit and betaglycan, both of which are antagonists of activin action. These data indicate that activin A acts as a PKC-induced paracrine factor involved in the suppression of CYP17A1 in the zona glomerulosa and can thereby contribute to functional adrenocortical zonation.

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“…Recently, Hofland et al demonstrated that ACTH levels were associated with adrenal levels of MC2R in adrenal hyperplasia samples (10). Therefore, we speculated that the decreased expression of MC2R was attributable to the suppression of ACTH before surgery.…”

Section: Discussionmentioning

confidence: 84%

A Rare Case of Adrenocorticotropic Hormone (ACTH)-independent Macroadrenal Hyperplasia Showing Ectopic Production of ACTH

et al. 2012

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A 57-year-old Japanese man presented with drug-resistant hypertension without Cushingoid features. Endocrinological tests revealed autonomous secretion of cortisol with suppressed plasma adrenocorticotropic hormone (ACTH). Imaging examinations showed multiple macronodules in the bilateral adrenal gland. These findings were consistent with subclinical Cushing's syndrome caused by ACTH-independent macronodular adrenal hyperplasia (AIMAH). Left adrenalectomy was performed and the resected adrenal lesion was consistent with the pathological diagnosis of AIMAH. Furthermore, in resected tissue, we demonstrated intraadrenal production of ACTH by immunohistochemical analysis and RIA. This is a very rare case of AIMAH showing ectopic production of ACTH, which may be associated with autonomous cortisol secretion.

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Melanocortin 2 Receptor-Associated Protein (MRAP) and MRAP2 in Human Adrenocortical Tissues: Regulation of Expression and Association with ACTH Responsiveness

Abstract: MRAP and MC2R expression is induced by ACTH and AngII, which would facilitate cell surface receptor availability. Physiological expression levels of MRAP, MRAP2, and MC2R were not limiting for ACTH sensitivity.

Cited by 26 publications

References 38 publications

Melanocortin receptor accessory proteins in adrenal gland physiology and beyond

Melanocortin receptor accessory proteins in adrenal gland physiology and beyond

Protein kinase C-induced activin A switches adrenocortical steroidogenesis to aldosterone by suppressing CYP17A1 expression

A Rare Case of Adrenocorticotropic Hormone (ACTH)-independent Macroadrenal Hyperplasia Showing Ectopic Production of ACTH

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