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)

The adrenal glands are a major source of steroid hormone biosynthesis. In normal physiology, the pituitary hormone corticotropin (ACTH) regulates the secretion of glucocorticoids via its G protein-coupled receptor (ACTHR), the product of the MC2R gene. Aldosterone is another major product of the adrenal gland; its regulation is controlled mainly by the renin-angiotensin system, although ACTH plays a role, too, especially under certain pathological conditions. The adrenal gland also secretes lesser amounts of androgens and intermediate metabolites of all these steroids. Unregulated secretion of any of these hormones can be caused by tumors, adrenocortical adenomas or carcinomas, and/or bilateral (or, rarely, unilateral) hyperplasia. Cortisol-producing hyperplasia of the adrenal glands is caused by two distinct syndromes, both of which have been directly or indirectly associated with protein kinase A signaling: (i) primary pigmented nodular adrenocortical disease (PPNAD) (a micronodular form of bilateral adrenal hyperplasia), either isolated (rarely) or in the context of Carney complex, is caused (in most cases) by mutations of the PRKAR1A gene; and (ii) ACTH-independent macronodular adrenal hyperplasia (AIMAH), or massive macronodular adrenal disease (MMAD), has been associated with aberrant (ectopic) expression, and presumably regulation, of various G protein-coupled receptors. AIMAH is a rare, sporadic condition affecting predominantly middle-aged men and women with an almost equal ratio (the latter in contrast to other forms of endogenous Cushing's syndrome). Some familial cases of AIMAH have also been described, and it appears that the pathophysiological phenomena underlying AIMAH may be present in the far more common, sporadic adrenocortical tumors and, perhaps, in the nodular growth detected in the adrenal glands of the elderly in the general population. Thus, the study of ectopic receptor expression and cAMP-dependent PKA activity in AIMAH may have wider implications for adrenal and, indeed, endocrine tumorigenesis.
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PMID:Cyclic AMP-dependent signaling aberrations in macronodular adrenal disease. 1211 80

In several cases of familial glucocorticoid deficiency (FGD), referred to as FGD type 1, mutations have been described in the coding exon of the adrenocorticotropin receptor (melanonocortin receptor type 2, MC2R) gene. However, for the majority of cases (FGD type 2), no mutations were found in this gene. In the more informative families, the involvement of the MC2R locus could be excluded by linkage or sequencing analysis and, as there was no obvious candidate gene, a genome linkage scan was performed. Fourteen families were studied in this report. Evidence of linkage was found with markers on chromosome 8q in three out of the 14 families (maximum heterogeneity LOD score of 2.81 at D8S1763). These three families were consanguineous and the gene could be located by homozygosity mapping between markers D8S285 and D8S1718 in a 8.8-cM region. No potential candidate genes were apparent in the region. Linkage to this region could be excluded in some families from our sample giving highly negative LOD scores with the markers of the region. This result suggests that at least one other gene, located on a different region, must be responsible for FGD in these families and provides new evidence of genetic heterogeneity of this disorder.
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PMID:Linkage of one gene for familial glucocorticoid deficiency type 2 (FGD2) to chromosome 8q and further evidence of heterogeneity. 1238 87

Familial glucocorticoid deficiency (FGD) is a rare autosomal recessive disorder characterized by glucocorticoid deficiency, elevated plasma adrenocorticotropic hormone (ACTH) levels and preserved aldosterone/renin secretion. Adrenocorticotropic receptor mutations occur in about 40% of patients (FGD type 1), whereas the rest of the cases are associated with a normal receptor (FGD type 2). More than 50 cases have been reported in the literature so far. We report two cases of type 2 FGD from two related families who presented in the newborn period with varying clinical features. Direct sequencing of the genomic DNA of the patients failed to reveal mutations or other defects in the coding sequence of the ACTH receptor. Linkage analysis excluded mutations on the MC2-R gene outside the coding region. To our knowledge, these are the first two cases of FGD reported from the Middle East.
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PMID:Familial glucocorticoid deficiency type 2 in two neonates. 1255 30

Zebrafish are an excellent genetic model system for studying developmental and physiological processes. Pigment patterns in zebrafish are affected by mutations in three types of chromatophores. The behavior of these cells is influenced by alpha-melanocyte-stimulating hormone (alphaMSH) and melanin-concentrating hormone (MCH). Mammals have five alphaMSH receptors (melanocortin receptors) and one or two MCH receptors. We have identified the full complement of melanocortin and MCH receptors in both zebrafish and the pufferfish, Fugu. Zebrafish have six melanocortin receptors, including two MC5R orthologues, while Fugu, lacking MC3R, has only four. We also demonstrate that Fugu and zebrafish have two and three MCHR genes, respectively. MC2R and MC5R are physically linked in all species examined. Unlike other species, we find the Fugu genes contain introns, one of which is in a conserved location and is probably ancestral. We also detail the differential expression of the zebrafish genes throughout development.
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PMID:The structure and evolution of the melanocortin and MCH receptors in fish and mammals. 1262 Mar 96

It is known that the stress hyporesponsive period (SHRP), which seems to be related to an immature hypothalamo-pituitary-adrenal (HPA) regulatory system, occurs during the first 2 weeks after birth in rats. 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 cyclic adenosine 3',5'-monophosphate (cAMP), corticosterone, and adenylate cyclase activity increased with the dose of ACTH in adrenal cells of males and females in vitro. The ACTH responsiveness in adrenal cells increased with age (7-35 days of age), that is, the loss in responsiveness to ACTH just after birth began to recover in 14-35-day-old rats, but the responsiveness in 14-day-old rats was attenuated in males compared with females. Although castration markedly augmented the responsiveness in male rats, testosterone-replacement in the castrated male rats inhibited the enhancement. Furthermore, the responsiveness in 14-day-intact female rats was suppressed by treatment with testosterone. Expression levels of ACTH receptor mRNA in adrenals increased with age in the female rat, but not in the male. Castration enhanced the level of ACTH receptor mRNA to three-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. Testicular androgens are thought to evoke a gender-specific response in neonates, and the temporal decrease of adrenal ACTH-responsiveness might be due to the topically immature adrenal system as well as the central nervous system in mammals.
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PMID:Sex-differences in adrenocortical responsiveness during development in rats. 1279 94

The melanocortin (MC) gamma3-MSH is believed to signal through the MC3 receptor. We showed that it induces a sustained increase in intracellular free calcium levels ([Ca(2+)](i)) in a subpopulation of pituitary cells. Most of the cells responding to gamma3-MSH express more than one pituitary hormone mRNA. The effect of gamma3-MSH is blocked by SHU9119, a MC3R and MC4R antagonist, in only 50% of the responsive cells, suggesting that in half of these cells the mediating receptor is not the MC3R. Low picomolar doses of gamma3-MSH increase [Ca(2+)](i) in the growth hormone (GH)- and prolactin (PRL)-secreting GH3 cell line. gamma2-MSH and alpha-MSH display a similar effect. SHU9119 does not affect the gamma3-MSH-induced [Ca(2+)](i) response. MTII, a potent synthetic agonist of the MC3R, MC4R, and MC5R, also shows no or low potency in increasing [Ca(2+)](i). By means of RT-PCR, the mRNA of the MC2R, MC3R, and MC4R receptors is undetectable. Experiments testing gamma2-MSH analogues with single alanine replacements show that, unlike the classic MCRs, the His(5)-Phe(6)-Arg(7)-Trp(8) sequence in gamma2-MSH is not a core sequence for activating the gamma-MSH receptor in GH3 cells, whereas Met(3) is essential. Low nanomolar doses of gamma-MSH increase intracellular cAMP levels. Blockade of protein kinase A abolishes the [Ca(2+)](i) responses to gamma3-MSH. gamma2-MSH increases binding of [S(35)]GTPgammaS to membrane preparations of GH3 cells. The pharmacological characteristics of gamma-MSH peptides and analogues on [Ca(2+)](i) and the signal-transduction pathways present strong evidence for the expression of a hitherto uncharacterized gamma-MSH receptor in GH3 cells, belonging to the G protein-coupled receptor family.
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PMID:Gamma-MSH peptides in the pituitary: effects, target cells, and receptors. 1285 7

Adult Leydig cell steroidogenesis is dependent on LH but fetal Leydig cells can function independently of gonadotropin stimulation. To identify factors that may be involved in regulation of fetal Leydig cells expressed sequence tag libraries from fetal and adult testes were compared, and fetal-specific genes identified. The ACTH receptor [melanocortin type 2 receptor (Mc2r)] was identified within this fetal-specific group. Subsequent real-time PCR studies confirmed that Mc2r was expressed in the fetal testis at 100-fold higher levels than in the adult testis. Incubation of fetal or neonatal testes with ACTH in vitro stimulated testosterone production more than 10-fold, although ACTH had no effect on testes from animals aged 20 d or older. The steroidogenic response of fetal and neonatal testes to a maximally stimulating dose of human chorionic gonadotropin was similar to the response shown to ACTH. The ED(50) for ACTH, measured in isolated fetal and neonatal testicular cells, was 5 x 10(-10) M and the lowest dose of ACTH eliciting a response was 2 x 10(-11) M. Circulating ACTH levels in fetal mice were around 8 x 10(-11) M. Neither alpha-MSH nor gamma-MSH had any effect on androgen production in vitro at any age. Fetal testosterone levels were normal in mice that lack circulating ACTH (proopiomelanocortin-null) indicating that ACTH is not essential for fetal Leydig cell function. Results show that both LH and ACTH can regulate testicular steroidogenesis during fetal development in the mouse and suggest that fetal Leydig cells, but not adult Leydig cells, are sensitive to ACTH stimulation.
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PMID:Adrenocorticotropic hormone directly stimulates testosterone production by the fetal and neonatal mouse testis. 1286 1

Adrenocorticotropic hormone (ACTH) induces lipolysis in a dose-dependent fashion in rodent adipose tissue and adipocytes in vitro. The role of ACTH on lipolysis in human adipose tissue is less clear, however. In this study, we address the hypothesis that ACTH induces lipolysis in human adipose tissue. We used ex vivo organ culture to examine lipolysis in human and mouse adipose tissue. Adipose tissue fragments suspended in culture medium and human ACTH, isoproterenol (positive control), or insulin (negative control) was added in varying concentrations. Lipolysis was measured using glycerol appearance. ACTH receptor mRNA expression was assessed using reverse-transcription polymerase chain reaction (RT-PCR). In mouse adipose tissue, ACTH induced lipolysis in dose-dependent manner; 100 pmol/l ACTH induced 67+/-19% of isoproterenol-stimulated lipolysis and 500 pmol/l ACTH: 86+/-13%. In contrast, human adipose tissue shared no significant response to 100 pmol/l ACTH; ACTH was associated with 9+/-6% and 500 pmol/l of ACTH, 8+/-6% of isoproterenol-stimulated lipolysis. ACTH receptor mRNA was present in mouse adipose tissue, but undetectable in human adipose tissue. These results suggest lipolysis regulation differs between human and mouse adipose tissue in response to ACTH.
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PMID:Differential effects of adrenocorticotropic hormone on human and mouse adipose tissue. 1292 81

The melanocortins are a group of small protein hormones derived by post-translational cleavage of the proopiomelanocortin (POMC) gene product. The known melanocortin hormones include alpha-melanocyte stimulating hormone (MSH), beta-MSH, gamma-MSH and adrenocorticotropic hormone (ACTH). Five melanocortin receptors (MCIR through to MC5R) have been identified and most of these show tissue-specific expression patterns, as well as different binding affinities for each of the melanocortin hormones. The central melanocortin system consists of alpha-MSH, agouti-related protein (AGRP), MC3R and MC4R. AGRP and alpha-MSH are believed to be the natural antagonist and agonist respectively of MC3R and MC4R. This central melanocortin system is thought to play a fundamental role in the control of feeding and body weight. Knock-out mice models and genetic studies have pointed to the importance of the melanocortins in complex human pathways such as pigmentation, lipolysis, food intake, thermogenesis, sexual behaviour, memory and inflammatory response. Recently the melanocortins and their receptors have been the target for drug-based treatment of human physiological processes. MC3R and MC4R are likely targets for controlling body weight; MCIR may be used in the treatment of inflammation and MC2R for the treatment of glucocortical deficiency. A role for MCSR still remains unclear, but the evidence suggests an exocrine gland function.
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PMID:Melanocortins and their receptors and antagonists. 1453 56

The G-protein-coupled melanocortin receptors (MCRs) play an important role in a variety of essential functions such as the regulation of pigmentation, energy homeostasis, and steroid production. We performed a comprehensive characterization of the MC system in Fugu (Takifugu rubripes). We show that Fugu has an AGRP gene with high degree of conservation in the C-terminal region in addition to a POMC gene lacking gamma-MSH. The Fugu genome contains single copies of four MCRs, whereas the MC3R is missing. The MC2R and MC5R are found in tandem and remarkably contain one and two introns, respectively. We suggest that these introns were inserted through a reverse splicing mechanism into the DRY motif that is widely conserved through GPCRs. We were able to assemble large blocks around the MCRs in Fugu, showing remarkable synteny with human chromosomes 16 and 18. Detailed pharmacological characterization showed that ACTH had surprisingly high affinity for the Fugu MC1R and MC4R, whereas alpha-MSH had lower affinity. We also showed that the MC2R gene in Fugu codes for an ACTH receptor, which did not respond to alpha-MSH. All the Fugu receptors were able to couple functionally to cAMP production in line with the mammalian orthologs. The anatomical characterization shows that the MC2R is expressed in the brain in addition to the head-kidney, whereas the MC4R and MC5R are found in both brain regions and peripheral tissues. This is the first comprehensive genomic and functional characterization of a GPCR family within the Fugu genome. The study shows that some parts of the MC system are highly conserved through vertebrate evolution, such as regions in POMC coding for ACTH, alpha-MSH, and beta-MSH, the C-terminal region of AGRP, key binding units within the MC1R, MC2R, MC4R, and MC5R, synteny blocks around the MCRs, pharmacological properties of the MC2R, whereas other parts in the system are either missing, such as the MC3R and gamma-MSH, or different as compared to mammals, such as the affinity of ACTH and MSH peptides to MC1R and MC4R and the anatomical expression pattern of the MCRs.
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PMID:The melanocortin system in Fugu: determination of POMC/AGRP/MCR gene repertoire and synteny, as well as pharmacology and anatomical distribution of the MCRs. 1469 81


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