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) is an autosomal recessive syndrome of failure of adrenal cortisol responsiveness to adrenocorticotropin (ACTH). Defects in the ACTH receptor have been suggested as a possible cause, and we have previously reported a point mutation in this gene in a family with FGD. Investigation of seven additional families has revealed a number of novel mutations in the ACTH receptor in some, but a normal gene in others suggesting that the aetiology of FGD may be heterogeneous. Using a highly polymorphic CA repeat marker (D18S40) closely linked to the ACTH receptor locus, we are now able to confirm that some cases of FGD result from defects at another locus. FGD provides an example of a single relatively homogeneous clinical syndrome resulting from two different molecular aetiologies.
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PMID:Mutations of the ACTH receptor gene are only one cause of familial glucocorticoid deficiency. 806 3

Familial glucocorticoid deficiency is an uncommon disorder that appears to be due to congenital insensitivity or resistance to adrenocorticotropin (ACTH), and is usually inherited in an autosomal recessive pattern. We investigated the DNA base sequence in a family with this condition by polymerase chain reaction amplification of DNA with pairs of primers that span the ACTH-receptor domain. The affected male proband showed a single base mutation, ser74-->ile, in the sequence coding for the second transmembrane domain of the ACTH receptor. A similar defect was found in an affected sister, a normal sequence in an unaffected brother, and both alleles in each parent. This is only the second clinical disorder associated with a GTP-binding-protein-linked hormone-receptor mutation.
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PMID:Familial glucocorticoid deficiency associated with point mutation in the adrenocorticotropin receptor. 809 89

1. Adrenocortical membrane protein was isolated from the adrenal glands of 12 Large White x Landrace male pigs, six with high adrenocortical response to adrenocorticotropic hormone (ACTH) and six with low response. 2. The peptide (Phe2, Nle4) ACTH was iodinated by the chloramine-T method and served as the radioligand in receptor binding studies. 3. Only one class of ACTH receptor was detected, with Kd = 2.57 +/- 0.35 x 10(9) M and Bmax = 1.59 +/- 0.06 pmol/mg protein in high responders and Kd = 1.68 +/- 0.18 x 10(-9) M and Bmax = 1.17 +/- 0.11 pmol/mg protein in low responders. 4. The difference in the Bmax between high and low responders was significant (P < 0.05), the difference in Kd was not statistically significant.
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PMID:Adrenocortical ACTH receptors in pigs of differing in vivo response to adrenocorticotropin. 809 60

VIP dose-dependently increased basal, but not submaximally ACTH (10(-10) M)-stimulated, aldosterone (ALDO) and corticosterone (B) secretion of dispersed rat capsular and inner adrenocortical cells, respectively. The maximal stimulatory effect (60-70% rise) was obtained with a VIP concentration of 10(-8) M. [4-Cl-D-Phe6,Leu17]-VIP, a VIP-receptor antagonist (VIP-A), and corticotropin-inhibiting peptide (CIP), an ACTH receptor antagonist (both 10(-6) M), completely annulled VIP (10(-8) M)-evoked rises in basal ALDO and corticosterone secretions. The ACTH (10(-10) M)-enhanced (about 5-fold) production of both hormones was completely reversed by CIP (10(-6) M) and only partially reduced (about -30%) by VIP-A (10(-6) M). The hypothesis is advanced that the weak secretagogue effect of VIP on dispersed rat capsular and inner adrenocortical cells may be due to its positive interaction with ACTH receptors.
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PMID:Stimulatory effect of vasoactive intestinal peptide (VIP) on the secretory activity of dispersed rat adrenocortical cells. Evidence for the interaction of VIP with ACTH receptors. 818 Jan 11

Recent studies have revealed the presence of four subtypes for the melanocortin receptor (MC-R). Among these MC-Rs, MC2-R is considered to be an adrenocorticotropin (ACTH) receptor because its expression is almost localized in the adrenal cortex. Five Japanese patients with ACTH unresponsiveness were examined as to whether they have mutations in the putative ACTH receptor. Among these patients, there are two groups of siblings, each of which consists of two individuals. The coding region of the ACTH receptor gene was amplified by polymerase chain reaction and directly sequenced on both strands, however, no point mutation was found in any of the five patients, suggesting that familial glucocorticoid deficiency, caused by the mutated ACTH receptor, may be rare.
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PMID:[Adrenocorticotropin receptor in familial glucocorticoid deficiency]. 825 33

Corticotropin (ACTH) receptors have been characterized by covalent cross-linking of radiolabeled ACTH ([125I]ACTH) with the bifunctional cross-linking reagent disuccinimidyl suberate to cultured bovine adrenal fasciculata reticularis cells (BAC), and to crude plasma membrane fractions prepared from both human and bovine adrenals. Incubation of BAC with [125I]ACTH at 20 degrees C followed by cross-linking resulted in the specific labeling of two binding proteins with apparent M(r) of 154,000 and 43,000 as measured by SDS-PAGE under reducing and non-reducing conditions. In addition, in some experiments another band with an apparent M(r) of 124,000 was observed. All of these bands disappeared when the incubation was performed in the presence of an excess of unlabeled ACTH. When BAC were incubated with [125I]ACTH in the presence of 100 microM phenylarsine oxide at 20 degrees C, a condition which prevents the internalization of the ACTH-receptor complex, the bulk of the radioactivity was present in the 43,000 band. After [125I]ACTH cross-linking to BAC, subcellular preparations followed by SDS-PAGE revealed that the 20,000 g fraction contained mainly the 43,000 M(r) form. Cross-linking of [125I]ACTH to plasma membrane-enriched fractions prepared from human and bovine adrenals resulted only in the labeling of the 43,000 protein. These results indicate that the ACTH receptor present at the cell surface is a macromolecule of 43,000, and suggest that the 154,000 form probably represents association of the ACTH-receptor complex to another macromolecule. The 154,000 protein would be formed during or after internalization of the ACTH-receptor complex.
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PMID:Identification and characterization of corticotropin receptors in bovine and human adrenals. 838 Oct 13

Developmental changes in the responsiveness of the fetal adrenals to corticotropin (ACTH) play an important role in the regulation of the fetal hypothalamic-pituitary-adrenal axis. Responsiveness of adrenal cortical cells to ACTH is dependent on the extent of ACTH receptor expression. Therefore, we examined the localization and regulation of ACTH receptor expression in the midgestation (16-24 weeks) human fetal adrenal cortex. In situ hybridization analysis was used to localize messenger RNA (mRNA) encoding the ACTH receptor in sections of human fetal adrenal glands. Messenger RNA encoding the ACTH receptor was localized in cells from all cortical zones; abundance was higher in definitive zone than in fetal zone cells and was least abundant in the more central portions of the cortex. Regulation of ACTH receptor expression was studied using Northern blot analysis of total RNA extracted from primary cultures of fetal and definitive zone cells. Two major (1.5 and 3.5 kilobases) and, upon stimulation with ACTH, 3 minor (4.0, 6.0 and 10.0 kb) ACTH receptor mRNA transcripts were detected in RNA from fetal and definitive zone cells. In both cell types, ACTH-(1-24) increased the abundance of mRNA encoding the ACTH receptor 10- to 20-fold compared with untreated cells. The effects of ACTH-(1-24) on ACTH receptor expression in fetal zone cells were time- and dose-dependent. The ED50 for the stimulation of ACTH receptor expression by ACTH-(1-24) was 1-10 pM, and maximal response to 0.1 nm ACTH-(1-24) was detected after 12-16 h. Eight-bromoadenosine cAMP and forskolin also stimulated ACTH receptor expression in fetal zone cells and closely mimicked the effects of ACTH-(1-24). In contrast, stimulation of protein kinase C with 12-O-tetradecanoyl phorbol 13-acetate had no effect on ACTH receptor expression. Changes in ACTH receptor expression in response to ACTH-(1-24), cAMP and forskolin were paralleled by changes in expression of the P450 cholesterol side chain cleavage (P450scc) enzyme. These data demonstrate that expression of the ACTH receptor by the human fetal adrenal cortex is up-regulated by its own ligand and that this effect is mediated by a cAMP-dependent mechanism. In addition, the coordinate stimulation of ACTH receptor and P450scc expression by ACTH indicates that the gene for the ACTH receptor is one of a specific cohort of genes regulated by ACTH that are required to facilitate fetal adrenal cortical response to ACTH. ACTH regulation of its own receptor may represent a mechanism by which fetal adrenal responsiveness to ACTH is maintained and possibly enhanced during fetal development.
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PMID:Localization and regulation of corticotropin receptor expression in the midgestation human fetal adrenal cortex: implications for in utero homeostasis. 855 Jul 75

It has been known for many years that adipocytes express high affinity ACTH and alpha-melanocyte stimulating hormone (MSH) binding sites, and that ACTH, alpha-MSH, and beta-lipotropin are potent lipolytic hormones. We show here that the adipocyte response to the melanocortin peptides results from the expression of both the MC2 (ACTH) receptor as well as the newly discovered MC5 receptor. Using RT-PCR and Northern blot hybridization, high levels of MC2 receptor messenger RNA (mRNA) were found in all adipose tissues examined in the mouse, whereas MC5 receptor mRNA was found in a subset of these. Both receptors mRNAs were also found in the 3T3-L1 cell line but only after the cells had been induced to differentiate into adipocytes. This cell line was then used to characterize the pharmacological properties of the MC2 and MC5 receptor sites in situ. The MC2 receptor exhibits properties similar to the ACTH receptor characterized in adrenocortical cells, coupling to activation of adenylyl cyclase with an EC50 of approximately 1 nM. An MSH binding site characterized in these cells is presumably the MC5 receptor, based on the observation that this is the only other melanocortin receptor mRNA detected in these cells. The MC5 receptor in the 3T3-L1 adipocyte activated adenylyl cyclase in response to alpha-MSH stimulation. Interestingly, Nle4, D-Phe7-alpha-MSH (NDP-MSH), a commonly used synthetic alpha-MSH agonist, was a potent antagonist of the MC5 receptor expressed in the 3T3-L1 cell line. Although the agouti signaling peptide is a potent antagonist of NDP-MSH binding to the MC1 and MC4 melanocortin receptors, agouti was unable to block NDP-MSH binding in the 3T3-L1 adipocyte.
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PMID:Characterization of melanocortin receptor subtype expression in murine adipose tissues and in the 3T3-L1 cell line. 861 46

Using cultured bovine adrenal fasciculata cells (BAC), we investigated the effects of two hormones, corticotropin (ACTH) and angiotensin II (Ang-II) and two growth factors, insulin-like growth factors I (IGF-I) and transforming growth factor beta 1 (TGF beta 1), on the mRNA levels of nuclear proto-oncogenes of the Fos and Jun families and on the mRNA levels of genes expressed in BAC coding for ACTH and AT1 receptors, cytochrome P450scc and P450 17 alpha and 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD). ACTH and IGF-1 increased c-fos and jun-B mRNA levels early with later increases in the levels of mRNA for the ACTH receptor and the three steroidogenic enzymes, and enhanced steroidogenic responses to both ACTH and Ang-II. In contrast, Ang-II increased mRNA coding for the three proto-oncogenes (cfos, c-jun, and jun-B), decreased those for P450 17 alpha and 3 beta-HSD, and caused marked homologous and heterologous steroidogenic desensitization. TGF beta 1 increased only jun-B mRNA and markedly reduced BAC-differentiated functions and steroidogenic responsiveness to both ACTH and Ang-II. The long-term effects of ACTH on human adrenal fasciculata cells were comparable with those observed in BAC, whereas the long term effects of Ang-II and TGF beta 1 were different from those observed in BAC. Whether these species-specific differences are related to a different effect of these factors on proto-oncogene expression is not yet known.
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PMID:Regulation of primary response and specific genes in adrenal cells by peptide hormones and growth factors. 873 96

The present study was undertaken to examine the mechanism whereby beta-lipotropin stimulates adrenal steroidogenesis. In guinea pig adrenal cells, beta-lipotropin (10(-8) M) increased basal steroid production 6-, 4-, and 5-fold for cortisol, androstenedione, and dehydroepiandrosterone (DHEA), respectively, whereas the corresponding responses to adrenocorticotropin (ACTH) (10(-9) M) were 12-, 8-, and 7-fold. The conversion of cholesterol to pregnenolone was studied in cells treated with trilostane, an inhibitor of 3 beta-hydroxysteroid delta 4-5 isomerase. beta-Lipotropin (10(-10) and 10(-8) M) and ACTH (10(-9) M) stimulated pregnenolone production in trilostane-treated cells. The production of cortisol and androgens from precursor steroids was also studied in cells treated with aminoglutethimide, an inhibitor of cholesterol side chain cleavage, after addition of exogenous pregnenolone, 17-hydroxypregnenolone, progesterone, or DHEA. Neither ACTH nor beta-lipotropin stimulated cortisol, androstenedione, or DHEA production in the presence of exogenous precursors in aminoglutethimide-treated cells. No inhibition of the beta-lipotropin- or ACTH-stimulated cortisol or androstenedione responses was demonstrated with the opioid receptor antagonist naloxone (10(-11) to 10(-5) M). The results suggest that beta-lipotropin stimulates steroidogenesis by acting on the conversion of cholesterol to pregnenolone and that its effects are not mediated via an opioid receptor but may be mediated via an ACTH receptor.
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PMID:beta-Lipotropin-stimulated adrenal steroid production. 873 40


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