Familial Glucocorticoid Deficiency: Advances in the Molecular Understanding of ACTH Action

Chan, Li F.; Clark, A. J. L.; Metherell, Louise A.

doi:10.1159/000111810

Cited by 50 publications

(48 citation statements)

References 122 publications

(77 reference statements)

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“…Type 2 familial glucocorticoid deficiency shows an autosomal recessive pattern of inheritance (1,2). To date, all of the diseasecausing mutations identified in MRAP would produce no protein or a severely truncated MRAP molecule (1,26).…”

Section: Discussionmentioning

confidence: 99%

“…Unless adrenal corticosteroids are replaced, the failure to respond to ACTH can lead to hypoglycemia, infection, and death. Some individuals with familial glucocorticoid deficiency (type 1) have inactivating mutations in the MC2 receptor (1)(2)(3). As shown by Metherell et al (4), another group of patients with familial glucocorticoid deficiency (type 2) has mutations in a protein needed for MC2 receptor function, termed MRAP (melanocortin 2 receptor accessory protein) (1,2).…”

mentioning

confidence: 99%

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Regions of Melanocortin 2 (MC2) Receptor Accessory Protein Necessary for Dual Topology and MC2 Receptor Trafficking and Signaling

Sebag

Hinkle

2009

Journal of Biological Chemistry

113

154

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MRAP, melanocortin 2 (MC2) receptor accessory protein, is required for trafficking by the MC2 (ACTH) receptor. MRAP is a single transmembrane protein that forms highly unusual antiparallel homodimers. We used molecular complementation to ask where MRAP achieves dual topology. Fragments of yellow fluorescent protein (YFP) were fused to the NH 2 or COOH terminus of MRAP such that YFP fluorescence could occur only in antiparallel homodimers; fluorescence was present in the endoplasmic reticulum. MRAP retained dual topology after deletion of most of the amino terminus. In contrast, deletion of residues 31-37, just NH 2 -terminal to the transmembrane domain, forced MRAP into a single N exo /C cyt orientation and blocked its ability to promote MC2 receptor trafficking and homodimerize. When the transmembrane domain of MRAP was replaced with the corresponding region from RAMP3, dual topology was retained but MRAP was inactive. Insertion of MRAP residues 29 -37 conferred dual topology to RAMP3, normally Pituitary adrenocorticotropic hormone (ACTH)2 activates melanocortin 2 (MC2) receptors in the adrenal cortex, stimulating the biosynthesis of glucocorticoids. In familial glucocorticoid deficiency, patients are resistant to ACTH and unable to make sufficient glucocorticoids. Unless adrenal corticosteroids are replaced, the failure to respond to ACTH can lead to hypoglycemia, infection, and death. Some individuals with familial glucocorticoid deficiency (type 1) have inactivating mutations in the MC2 receptor (1-3). As shown by Metherell et al. (4), another group of patients with familial glucocorticoid deficiency (type 2) has mutations in a protein needed for MC2 receptor function, termed MRAP (melanocortin 2 receptor accessory protein) (1, 2).MRAP is required for MC2 receptor maturation and trafficking to the plasma membrane (4 -6). It is a small protein containing a single transmembrane domain with no signal peptide. In the absence of MRAP, MC2 receptor is retained in the endoplasmic reticulum (ER), lacks mature carbohydrate, and is rapidly degraded. In the presence of MRAP, MC2 receptor is glycosylated and localized on the plasma membrane, where it binds ACTH and activates adenylyl cyclase (6).The NH 2 -terminal and transmembrane segments of MRAP are strongly conserved, whereas the COOH-terminal domains are highly divergent and apparently nonessential. Two splice variants of human MRAP that differ completely in the region COOH-terminal to the transmembrane region (5) and a truncated mouse MRAP lacking the entire COOH terminus (6) promote surface expression and signal transduction by the MC2 receptor. MRAP forms a stable, immunoprecipitable complex with the MC2 receptor (4, 6, 7). The MC2 receptor is one of five melanocortin receptors, class A G protein-coupled receptors (GPCRs) that are coupled to G proteins and cause an increase in cAMP when activated (8). ACTH is the natural agonist for the MC2 receptor, whereas the various melanocyte-stimulating hormone peptides bind with high affinity to all other melanocortin ...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Regions of Melanocortin 2 (MC2) Receptor Accessory Protein Necessary for Dual Topology and MC2 Receptor Trafficking and Signaling

Sebag

Hinkle

2009

Journal of Biological Chemistry

113

154

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“…Age of onset of symptoms ranges from birth to nine years, but majority occur in first five years [2]. [1,4]. On histopathology it is seen that zona fasciculata and zona reti.cularis of adrenal gland are markedly atrophic while zona glomerulosa is well preserved leading to low plasma cortisol concentrations.…”

Section: Introductionmentioning

confidence: 99%

“…Adrenal imaging in the form of MRIlCT scanning can be helpful. fu FGD the glands are usually small in size [8] in contrast to tuberculosis (calcified adrenal glands), CAH (eulargement), storage disorders and infiltrative disorders (enlargement of the gland) [1]. The mainstay of treatment in FGD is the replacement of glucocorticoids.…”

Section: Introductionmentioning

confidence: 99%

Familial Glucocorticoid Deficiency

Gupta

Khera

Kanitkar³

2011

Medical Journal Armed Forces India

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“…Improperly folded proteins are retained for refolding or degradation by the ubiquitin-proteosome pathway while properly folded proteins need to be exported from the ER to the cell surface (Castro-Fernandez et al, 2005;Conn et al, 2006). Inactivating mutations in GPCRs can lead to their intracellular retention and are known to give rise to a number of diseases including retinitis pigmentosa (rhodopsin receptor) (Mendes et al, 2005], hypogonadotropic hypogonadism (gonadotropin releasing hormone receptor) (Achermann et al, 2001), familial glucocorticoid deficiency (melanocortin 2 receptor) (Chan et al, 2008) and X-linked nephrogenic Diabetes insipidus (V2 vasopressin receptor) (Tan et al, 2004).…”

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confidence: 99%

Accessory proteins are vital for the functional expression of certain G protein-coupled receptors

Cooray

Chan

Webb

et al. 2009

Molecular and Cellular Endocrinology

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Familial Glucocorticoid Deficiency: Advances in the Molecular Understanding of ACTH Action

Cited by 50 publications

References 122 publications

Regions of Melanocortin 2 (MC2) Receptor Accessory Protein Necessary for Dual Topology and MC2 Receptor Trafficking and Signaling

Regions of Melanocortin 2 (MC2) Receptor Accessory Protein Necessary for Dual Topology and MC2 Receptor Trafficking and Signaling

Familial Glucocorticoid Deficiency

Accessory proteins are vital for the functional expression of certain G protein-coupled receptors

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