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

alpha-Melanocyte stimulating hormone (MSH) and adrenocorticotropin (ACTH)1-24, the minimal ACTH sequence required for full activity, differ only by the 10 C-terminal amino acids of ACTH1-24. Interestingly, these ten C-terminal residues have been highly conserved throughout vertebrate evolution. To understand the functional constraints of these 10 amino acids we analyzed the effects of mutating these residues on steroidogenic activity in vivo and in vitro. Alanine substitutions of some of the first four amino acid residues (the basic core residues KKRR, 15-18) greatly reduces ACTH activity in vitro and in vivo; replacement of mutant alanines at residues 15 and 17 with glutamine residues partially restores ACTH activity. Thus, for ACTH receptor binding and activation, the amino acid residues 15-18 are important for their side chains. Surprisingly, conversion of the five C-terminal residues (20-24) to alanines increases ACTH activity in vivo over that of native ACTH. With respect to receptor binding and activity, the last five amino acid residues are important only for the peptide length they contribute; however, with respect to serum stability, their side chains are significant.
 ...
PMID:Mutational analysis of evolutionarily conserved ACTH residues. 1498 Jul 91

Mouse adrenocorticotropin receptor (ACTH-R/MC2R) messenger ribonucleic acid (mRNA) is expressed predominantly in the adrenal gland and, to a lesser extent, in adipose tissue. In this study, we found a novel 135-bp exon 1 (exon 1f) of the ACTH-R gene transcribed in mouse adipose tissue by RNA ligase-mediated rapid amplification of cDNA ends, which was located 1.4 kb downstream in the genome of previously-reported exon 1 (exon 1a) transcribed in the adrenal gland. The novel promoter region, 1.4 kb upstream of exon 1f contained three CCAAT boxes. RT-PCR analysis revealed that ACTH-R mRNA from adipose tissue and differentiated 3T3-L1 adipocytes exclusively contained exon 1f. Thus, the promoter region flanking to exon 1f is thought to be essential for adipose tissue, while that flanking to exon 1a is specific for the adrenal gland. A search for a similar sequence of mouse ACTH-R exon 1f and its flanking region in the human genome sequence database of GenBank Human Genome Resources did not reveal such a sequence in the region of the human ACTH-R gene. This may explain the absence of ACTH-R expression in human adipose tissue.
 ...
PMID:Alternate promoter and 5'-untranslated exon usage of the mouse adrenocorticotropin receptor gene in adipose tissue. 1500 5

It is not clear if an increase in intra-adrenal cortisol is required to mediate the actions of adrenocorticotropic hormone (ACTH) on adrenal growth and steroidogenesis during the prepartum stimulation of the fetal pituitary-adrenal axis. We infused metyrapone, a competitive inhibitor of cortisol biosynthesis, into fetal sheep between 125 and 140 days of gestation (term = 147 +/- 3 days) and measured fetal plasma cortisol, 11-desoxycortisol, and ACTH; pituitary pro-opiomelanocortin mRNA and adrenal expression of ACTH receptor (melanocortin type 2 receptor), steroidogenic acute regulatory protein (StAR), 11beta-hydroxysteroid dehydrogenase type 2 (11betaHSD2), cytochrome P450 cholesterol side-chain cleavage (CYP11A1), cytochrome P450 17-hydroxylase (CYP17), 3beta-hydroxysteroid dehydrogenase, and cytochrome P450 21-hydroxylase mRNA; and StAR protein in the fetal adrenal gland. Plasma ACTH and 11-desoxycortisol concentrations were higher (P < 0.05), whereas plasma cortisol concentrations were not significantly different in metyrapone- compared with vehicle-infused fetuses. The ratio of plasma cortisol to ACTH concentrations was higher (P < 0.0001) between 136 and 140 days than between 120 and 135 days of gestation in both metyrapone- and vehicle-infused fetuses. The combined adrenal weight and adrenocortical thickness were greater (P < 0.001), and cell density was lower (P < 0.01), in the zona fasciculata of adrenals from the metyrapone-infused group. Adrenal StAR mRNA expression was lower (P < 0.05), whereas the levels of mature StAR protein (30 kDa) were higher (P < 0.05), in the metyrapone-infused fetuses. In addition, adrenal mRNA expression of 11betaHSD2, CYP11A1, and CYP17 were higher (P < 0.05) in the metyrapone-infused fetuses. Thus, metyrapone administration may represent a unique model that allows the investigation of dissociation of the relative actions of ACTH and cortisol on fetal adrenal steroidogenesis and growth during late gestation.
 ...
PMID:Differential actions of metyrapone on the fetal pituitary-adrenal axis in the sheep fetus in late gestation. 1526 84

The authors report a case in which a patient harbored a corticotroph macroadenoma that secreted biologically inactive high-molecular-weight adrenocorticotropic hormone (ACTH) as well as authentic ACTH 1-39. The secretion of the high-molecular-weight ACTH was determined using gel chromatography. The authors believe that these two molecules competed with each other at the ACTH receptor and, thus, the bioactivity of ACTH 1-39 was masked and Cushing features were not manifested in the patient. This type of silent corticotroph adenoma may be categorized as a clinically nonfunctioning adenoma. Plasmas from patients with silent corticotroph adenomas, which are identified by positive immunohistochemical staining of ACTH, should be frozen, stored, and analyzed using gel chromatography to examine whether the tumors produce and secrete high-molecular-weight ACTH.
 ...
PMID:Secretion of high-molecular-weight adrenocorticotropic hormone from a pituitary adenoma in a patient without Cushing stigmata. Case report. 1554 Sep 32

We are increasingly exposed to environmental and occupational hazardous chemicals, which modulate hormonal activity and/or mutagenicity in mammals. In the present study, we investigated the effects of sex-steroid hormones on adrenocortical responsiveness to adrenocorticotropic hormone (ACTH) in neonatal rats. The levels of corticosterone increased with the dose of ACTH in adrenal cells of males and females in vitro. Although castration markedly augmented the responsiveness in male rats, testosterone-replacement in the castrated male rats inhibited the enhancement and, furthermore, the treatment with testosterone suppressed the responsiveness in 14-day-old intact female rats, too. Castration enhanced the level of ACTH receptor mRNA to 3-fold of that in intact male rats at 14 days of age, but replacement treatment with testosterone in castrated male rats lowered the elevated levels. These findings suggest that: 1) the hyporesponsiveness of adrenocorticosteroid in the stress hyporesponsive period of neonates might be dependent on the reduction of ACTH receptor mRNA, and 2) endocrine-disrupting chemicals, with characters of androgens, estrogens or gonadotropin-releasing hormones, might affect the responsiveness to ACTH and the ACTH receptor mRNA expression levels in adrenal cells of neonates.
 ...
PMID:Androgenic effects on adrenocortical responsiveness in neonatal rats. 1564 9

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.
 ...
PMID:Mutations in MRAP, encoding a new interacting partner of the ACTH receptor, cause familial glucocorticoid deficiency type 2. 1565 38

Dioxins and polychlorinated biphenyls (PCBs) have been shown to accumulate in the adrenal glands when incorporated into the body. However, the impacts of exposure on adrenal steroidogenesis have not been thoroughly investigated. In this study, we demonstrated that dioxin-like PCB126 altered androgen, cortisol, and aldosterone biosynthesis differentially in human adrenocortical H295R cells. PCB126 diminished basal and cAMP-induced androstenedione production as well as CYP17 mRNA expression in a dose-dependent and time-dependent manner. The CYP17 repression was accompanied with decreases in the encoded 17 alpha-hydroxylase and 17,20-lyase activities, particularly the latter. In contrast, high concentrations of PCB126 stimulated basal cortisol and aldosterone biosynthesis, including induction of CYP21B, CYP11B1, and CYP11B2 mRNA expression and elevation of the conversion of cortisol from 17-OH-progesterone and aldosterone from progesterone. cAMP abolished the positive effect of PCB126 on cortisol synthesis, while it synergistically enhanced PCB126 stimulation on CYP11B2 expression and aldosterone production. It seemed likely that the downregulation of CYP21B caused by the combination of PCB126 and cAMP counteracted the CYP11B1 induction stimulated by the co-treatment. In addition, high concentrations of PCB126 might sensitize the regulation of adrenocorticotropin (ACTH) on the adrenocortical cells by increasing ACTH receptor levels. Because adrenal steroids have profound influences on glucose tolerance, insulin sensitivity, lipid metabolism, obesity, vascular function, and cardiac remodeling, this article also discusses the potential association of the detected adrenocortical alterations with increased diabetic and cardiovascular risk found among highly exposed people.
 ...
PMID:PCB126 induces differential changes in androgen, cortisol, and aldosterone biosynthesis in human adrenocortical H295R cells. 1570 66

This study was conducted to examine stress-induced effects on gene expression of specific markers for HPA axis and neuronal activity in fetuses and neonatal pigs. Brain, pituitary gland, and adrenal gland were obtained to determine the mRNA levels for corticotropin-releasing hormone (CRH), CRH receptor 1 (CRHR1), pro-opiomelanocortin (POMC), ACTH receptor (MC2R), c-jun and c-fos. The suitability of these molecular markers was determined in neonatal pigs which were maternally deprived for two hours. It was found that maternal deprivation caused significantly higher transcript levels of c-fos and CRH in brain accompanied by a down-regulation of CRHR1 mRNA and an up-regulation of c-jun in the pituitary gland. To determine the effect of elevated maternal cortisol levels on gene expression of these molecular markers in fetuses, pregnant sows were treated with 100 IU ACTH (Synacthen Depot) s.c. every two days between Day 49 and Day 75 of gestation (normal gestation length 114 days). Animals were killed 48 hours after the last ACTH administration and fetuses of each sow were isolated. The ACTH treatment of sows significantly increased mRNA expression of c-fos but not of CRH in the fetal brain, and significantly decreased MC2R mRNA expression in the adrenal gland. However, HPA axis seems not to be fully developed in Day 77-fetuses because fetal pituitary CRHR1 and POMC mRNA expression was low in most of the fetuses. Although the expression of endocrine regulatory factors was partially incomplete in fetuses at the beginning of the third-trimester, ACTH dependent activation of c-fos mRNA in brain indicates a stress-related increase of neuronal activity. Based on these results it is assumed that prenatal stress in pigs may also have effects on the activity of the HPA axis in the offspring.
 ...
PMID:Stress-related gene expression in brain and adrenal gland of porcine fetuses and neonates. 1571 Feb 5

Adrenocorticotropic hormone (ACTH)-stimulated cortisol production by adrenal zona fasciculata cells requires coordinated biochemical and ionic signaling mechanisms that employ adenosine 3', 5'-cyclic monophosphate (cAMP) and Ca(2+) as intracellular messengers. As the primary messenger generated in response to ACTH receptor activation, cAMP acts at multiple sites to produce the full steroidogenic response that includes both rapid and delayed components. Biochemically, cAMP activates and induces the expression of multiple proteins that function in converting cholesterol to cortisol. These include the steroid acute regulatory (StAR) protein as well as steroidogenic enzymes. cAMP also inhibits a background K(+) channel (bTREK-1), which sets the resting potential of adrenal zona fasciculata (AZF) cells, thereby triggering membrane depolarization and Ca(2+) entry through voltage-gated Ca(2+) channels. Ca(2+) also accelerates the production of cortisol from cholesterol by activating or inducing the synthesis of steroidogenic proteins. In this scheme, background K(+) channels act pivotally by transducing a hormonal signal at the cell membrane to an ionic signal, leading to depolarization-dependent Ca(2+) entry. In this way, ACTH receptor activation increases cAMP and Ca(2+) in the AZF cell, yielding the full steroidogenic response. In addition to acutely regulating the activity of AZF cell ion channels, ACTH and cAMP also regulate the expression of genes coding for these ion channels. The tonic control of the expression of AZF cell ion channels through the hypothalamic-pituitary-adrenal axis suggests that prolonged stimulation of the AZF cell by ACTH may alter the electrical properties of these cells in a manner which matches the organism's requirement for cortisol.
 ...
PMID:Biochemical and Ionic signaling mechanisms for ACTH-stimulated cortisol production. 1572 7

Cortisol release from fish head kidney during the acute phase of the stress response is controlled by the adrenocorticotropic hormone (ACTH) from the pituitary pars distalis (PD). Alpha-melanocyte-stimulating hormone (alpha-MSH) and beta-endorphin, from the pars intermedia (PI), have been implicated in cortisol release during the chronic phase. The present study addresses the regulation of cortisol release by ACTH and alpha-MSH in common carp (Cyprinus carpio) and includes characterization of their receptors, namely, the melanocortin-2 and melanocortin-5 receptors (MC2R and MC5R). We could not demonstrate corticotropic activity of alpha-MSH, beta-endorphin, and combinations of these. We do show a corticotrope in the PI, but its identity is as yet uncertain. Carp restrained for 1 and 7 days showed elevated plasma cortisol and alpha-MSH levels; cortisol is still elevated but lower at day 7 than day 1 of restraint. Interrenal response capacity is unaffected, as estimated by stimulation with a maximum dose ACTH in a superfusion setup. MC2R and MC5R appear phylogenetically well conserved. MC2R is predominantly expressed in head kidney; a low abundance was found in spleen and kidney. MC5R is expressed in brain, pituitary PD, kidney, and skin. Quantitative PCR analysis of MC2R and MC5R expression in the head kidney of restrained fish reveals MC2R mRNA downregulation after 7 days restraint, in line with lower plasma cortisol levels seen. We discuss regulation of corticosteroid production from a phylogenetic perspective. We propose that increased levels of alpha-MSH exert a positive feedback on hypothalamic corticotropin-releasing hormone release to sustain a mild stress axis activity.
 ...
PMID:ACTH, alpha-MSH, and control of cortisol release: cloning, sequencing, and functional expression of the melanocortin-2 and melanocortin-5 receptor in Cyprinus carpio. 1589 Jul 86


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>