Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01189 (beta-endorphin)
 21,003 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Familial glucocorticoid deficiency (FGD), or hereditary unresponsiveness to adrenocorticotropin (ACTH; OMIM 202200), is an autosomal recessive disorder resulting from resistance to the action of ACTH on the adrenal cortex, which stimulates glucocorticoid production. Affected individuals are deficient in cortisol and, if untreated, are likely to succumb to hypoglycemia or overwhelming infection in infancy or childhood. Mutations of the ACTH receptor (melanocortin 2 receptor, MC2R) account for approximately 25% of cases of FGD. FGD without mutations of MC2R is called FGD type 2. Using SNP array genotyping, we mapped a locus involved in FGD type 2 to chromosome 21q22.1. We identified mutations in a gene encoding a 19-kDa single-transmembrane domain protein, now known as melanocortin 2 receptor accessory protein (MRAP). We show that MRAP interacts with MC2R and may have a role in the trafficking of MC2R from the endoplasmic reticulum to the cell surface.
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PMID:Mutations in MRAP, encoding a new interacting partner of the ACTH receptor, cause familial glucocorticoid deficiency type 2. 1565 38

The adrenocorticotropic hormone (ACTH) acts on adrenocortical cells and promotes steroidogenesis by specific binding to the ACTH (MC-2) receptor (ACTHR). To gain an insight into ACTH action on local steroidogenic organs, we examined the immunohistochemical expression of ACTHR in rat adrenal glands and placentas during the mid-late gestation period. Antibodies against synthetic ACTHR peptides were raised in rabbits, and Western blot analysis showed that the antibody reacted with specific proteins in the rat adrenal glands and placentas. The peroxidase-labeled antibody method revealed that ACTHR was distributed in the plasma membrane and cytoplasm of the parenchymal cells of the adrenocortical zona fasciculata. In the placenta, ACTHR was distributed in the junctional spongiotrophoblasts at day 13 of gestation--with a gradual decrease in the staining during the gestational period, whereas ACTHR appeared in the placental labyrinthine cells from days 15 to 19 of gestation. Immunoelectron microscopy revealed that ACTHR was also localized in the ribosomes of the fasciculata cells and the labyrinthine cells. Our findings suggest that ACTHR may play a physiological role in steroidogenesis in the adrenal cortical parenchymal cells as well as in the trophoblasts of rat placentas during mid-late gestation.
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PMID:Immunohistochemical localization of the ACTH (MC-2) receptor in the rat placenta and adrenal gland. 1578 85

The skin and its major appendages are prominent target organs and potent sources of key players along the classical hypothalamic-pituitary axis, such as corticotropin releasing hormone (CRH), adrenocorticotropic hormone (ACTH), and alpha melanocyte stimulating hormone (alpha-MSH), and even express key steroidogenic enzymes. Therefore, it may have established local stress response systems that resemble the hypothalamic-pituitary-adrenal (HPA) axis. However, functional evidence that this is indeed the case in normal human skin in situ has still been missing. We show that microdissected, organ-cultured human scalp hair follicles respond to CRH stimulation by up-regulating proopiomelanocortin (POMC) transcription and immunoreactivity (IR) for ACTH and alpha-MSH, which must have been processed from POMC. CRH, alpha-MSH, and ACTH also modulate expression of their cognate receptors (CRH-R1, MC1-R, MC2-R). In addition, the strongest stimulus for adrenal cortisol production, ACTH, also up-regulates cortisol-IR in the hair follicles. Isolated human hair follicles secrete substantial levels of cortisol into the culture medium, and this activity is further up-regulated by CRH. CRH also modulates important functional hair growth parameters in vitro (hair shaft elongation, catagen induction, hair keratinocyte proliferation, melanin production). Finally, human hair follicles display HPA axis-like regulatory feedback systems, since the glucocorticoid receptor agonist hydrocortisone down-regulates follicular CRH expression. Thus, even in the absence of endocrine, neural, or vascular systemic connections, normal human scalp hair follicles directly respond to CRH stimulation in a strikingly similar manner to what is seen in the classical HPA axis, including synthesis and secretion of cortisol and activation of prototypic neuroendocrine feedback loops.
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PMID:Human hair follicles display a functional equivalent of the hypothalamic-pituitary-adrenal axis and synthesize cortisol. 1594 90

The action of the peptide hormone adrenocorticotropin (ACTH) to stimulate glucocorticoid production by the adrenal gland is an essential physiologic process, yet is dependent on a single unique genetic component--the ACTH receptor or melanocortin 2 receptor. Genetic defects that cause abnormalities in this receptor or in a protein required for its expression at the cell surface result in a potentially fatal disease (familial glucocorticoid deficiency). Overexpression of this receptor or inability to desensitize it is found in adrenal adenomas or hyperplasia associated with glucocorticoid overproduction (Cushing syndrome). These disorders are uncommon, but there are considerable data to show that the hypothalamo-pituitary-adrenal axis is overactive, or in some circumstances underactive, in more common situations including depressive illness and septic shock. The origin of these latter disturbances is undoubtedly complex and multifactorial, but there is good evidence that a component of this phenomenon is an altered responsiveness of the ACTH receptor to ACTH. Understanding the basis of ACTH responsiveness might, therefore, contribute to the understanding of disorders such as these and perhaps enable the hypothalamo-pituitary-adrenal axis to be manipulated beneficially in these circumstances.
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PMID:Mechanisms of disease: the adrenocorticotropin receptor and disease. 1693 99

Inherited adrenocorticotropin (ACTH) resistance diseases are rare and include triple A syndrome and familial glucocorticoid deficiency (FGD). These conditions show genetic heterogeneity, i.e., the identical clinical phenotype may result from defects in more than one gene. Clinically, FGD is characterized only by ACTH resistance, while the triple A syndrome exhibits a variety of additional clinical features. FGD is caused by mutations in the ACTH receptor (melanocortin 2 receptor, MC2R) and the recently identified melanocortin 2 receptor accessory protein (MRAP) genes. In addition, linkage to a locus on chromosome 8 has been demonstrated. The identification of further genes in ACTH resistance syndromes may reveal novel aspects of MC2R signalling and trafficking. This review will summarize the clinical, biochemical and genetic aspects of these rare but informative diseases.
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PMID:The genetics of ACTH resistance syndromes. 1716 31

This study shows the characteristics of hormone-dependent lipolysis in white adipose tissues from corpulent spontaneously hypertensive rats (SHR/NDmc-cp(cp/cp)). The glycerol-releasing activity on addition of norepinephrine (NE) and corticotropin (ACTH) was diminished in slices of epididymal, retroperitoneal, and mesenteric adipose tissues from cp/cp rats compared with those from Wistar Kyoto rats and lean spontaneous hypertensive rats (SHR/NDmc-cp(+/+)). 8-Bromo-cyclic adenosine monophosphate had a slight effect on lipolysis in epididymal, retroperitoneal, and mesenteric adipose tissues from cp/cp rats, and addition of NE and ACTH resulted in a slight accumulation of cyclic adenosine monophosphate in epididymal adipose tissue from cp/cp rats. Therefore, the alteration of hormone-dependent lipolysis-related genes was analyzed using quantitative real-time polymerase chain reaction. It was found that the expression of beta(3)-adrenergic receptor, melanocortin 2 receptor, hormone-sensitive lipase, and perilipin messenger RNAs was limited in epididymal, retroperitoneal, mesenteric, and subcutaneous adipose tissues from cp/cp rats compared with +/+ rats. These results indicate that in white adipose tissue from cp/cp rats, the diminished lipolytic response to NE and ACTH may be caused by impaired expression of beta(3)-adrenergic receptor, melanocortin 2 receptor, hormone-sensitive lipase, and perilipin.
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PMID:Characteristics of lipolysis in white adipose tissues of SHR/NDmc-cp rats, a model of metabolic syndrome. 1751 19

The adrenocorticotropin (ACTH) receptor (melanocortin 2 receptor, or MC2R) is the smallest G-protein-coupled receptor that, when activated by the peptide hormone ACTH, stimulates cAMP production and adrenal steroidogenesis. Receptor expression is dependent on a specific membrane trafficking process involving an accessory protein (melanocortin 2 receptor accessory protein, or MRAP) and other unidentified components. In an attempt to discover novel receptor interacting proteins, the C-terminal tail of the MC2R was used to screen a mouse adrenal Y6 cell cDNA library using the bacterial two-hybrid system. This identified the nucleoporin Nup 50 (Npap60) as the major full-length interacting protein. Interaction was confirmed by a GST pulldown assay and by coimmunoprecipitation in human H295R cells (which express both proteins endogenously). Deletion analysis identified the region between residues 143 and 466 in Nup50 as being required for interaction with the MC2R. Stimulation of H295R cells with ACTH (10(-6) M) was followed by a gradual translocation of the Nup50-MC2R complex from the membrane to the nucleus after 30 min. This time course is most consistent with MC2R internalization dynamics and may suggest a novel role for Nup50.
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PMID:Interaction of the melanocortin 2 receptor with nucleoporin 50: evidence for a novel pathway between a G-protein-coupled receptor and the nucleus. 1762 72

ACTH (i.e., corticotropin) is the principal regulator of the hypothalamus-pituitary-adrenal axis and stimulates steroidogenesis in the adrenal gland via the specific cell-surface melanocortin 2 receptor (MC2R). Here, we generated mice with an inactivation mutation of the MC2R gene to elucidate the roles of MC2R in adrenal development, steroidogenesis, and carbohydrate metabolism. These mice, the last of the knockout (KO) mice to be generated for melanocortin family receptors, provide the opportunity to compare the phenotype of proopiomelanocortin KO mice with that of MC1R-MC5R KO mice. We found that the MC2R KO mutation led to neonatal lethality in three-quarters of the mice, possibly as a result of hypoglycemia. Those surviving to adulthood exhibited macroscopically detectable adrenal glands with markedly atrophied zona fasciculata, whereas the zona glomerulosa and the medulla remained fairly intact. Mutations of MC2R have been reported to be responsible for 25% of familial glucocorticoid deficiency (FGD) cases. Adult MC2R KO mice resembled FGD patients in several aspects, such as undetectable levels of corticosterone despite high levels of ACTH, unresponsiveness to ACTH, and hypoglycemia after prolonged (36 h) fasting. However, MC2R KO mice differ from patients with MC2R-null mutations in several aspects, such as low aldosterone levels and unaltered body length. These results indicate that MC2R is required for postnatal adrenal development and adrenal steroidogenesis and that MC2R KO mice provide a useful animal model by which to study FGD.
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PMID:Melanocortin 2 receptor is required for adrenal gland development, steroidogenesis, and neonatal gluconeogenesis. 1798 25

Preparing the mammalian fetus for birth requires an increase in fetal plasma glucocorticoid levels. The mechanisms facilitating this increase are not fully known. It has been shown in sheep that the prepartum elevation in fetal plasma cortisol is accompanied by increases in adrenocorticotropin receptor (ACTH-R) expression in the fetal adrenal and in the adrenal responsiveness to stimulation. To determine the significance of the upregulation in ACTH-R expression on fetal adrenal function, the authors used small interfering RNA targeted to the ovine ACTH-R to reduce receptor expression and studied responses to stimulation in ovine adrenal cells. They studied fetal cells from late gestation after responsiveness had increased. They also studied adult cells to determine if maturation would influence the impact of receptor expression suppression on responsiveness. Fetal and adult cells were obtained, dispersed, transfected with receptor-targeted small interfering RNA or scrambled small interfering RNA, and subsequently stimulated with ACTH. Cells and media were harvested for measurements of gene and protein expression and cyclic adenosine monophosphate (cAMP) and cortisol levels. The ability of ACTH to upregulate its receptor or steroid acute regulatory protein was attenuated in fetal (P < .01) and adult cells (P < .01) by small interfering RNA treatment; the blockade was more pronounced in the adult cells (P < .01). The small interfering RNA treatment also blocked the cAMP response to ACTH in fetal (P < .001) and adult (P < .05) cells. This was accompanied by marked reductions in cortisol responses in both (P < .001 and P < .01, respectively). These data suggest that upregulation of the ACTH-R expression in late gestation is essential for the increase in adrenal steroidogenic capacity occurring then. The data also indicate that a reduction in the ACTH-R expression blocks the ability of the peptide to stimulate early steps in the steroidogenic pathway event after maturation is complete.
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PMID:The impact of ACTH receptor knockdown on fetal and adult ovine adrenocortical cell function. 1842 Oct 20

Human adrenal development is a complex and relatively poorly understood process. However, significant insight into some of the mechanisms regulating adrenal development and function is being obtained through the analysis of individuals and families with adrenal hypoplasia. Adrenal hypoplasia can occur: (1) secondary to defects in pituitary adrenocorticotropin (ACTH) synthesis, processing and release (secondary adrenal hypoplasia; e.g. HESX1, LHX4, SOX3, TPIT, pituitary POMC, PC1); (2) as part of several ACTH resistance syndromes (e.g. MC2R/ACTHR, MRAP, Alacrima, Achalasia, Addison disease), or as (3) a primary defect in the development of the adrenal gland itself (primary adrenal hypoplasia; e.g. DAX1/NR0B1 - dosage-sensitive sex reversal, adrenal hypoplasia congenita critical region on the X chromosome 1). Indeed, the X-linked form of primary adrenal hypoplasia due to deletions or mutations in the orphan nuclear receptor DAX1 occurs in around half of male infants presenting with a salt-losing adrenal crisis, where no obvious steroidogenic defect (e.g. 21-hydroxylase deficiency), metabolic abnormality (e.g. neonatal adrenoleukodystrophy) or physical cause (e.g. adrenal haemorrhage) is found. Establishing the underlying basis of adrenal failure can have important implications for investigating associated features, the likely long-term approach to treatment, and for counselling families about the risk of other children being affected.
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PMID:Disorders of adrenal development. 1849 31


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