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 direct extra-adrenal actions of adrenocorticotropin 1-39 (ACTH) on electrical (E) and mechanical (M) characteristics of canine atrial tissues (AT) were investigated in in vitro experiments. One hundred twenty-five mU/ml of ACTH 1-39 significantly augmented the catecholamine induced positive inotropism as seen by shortening the time to peak tension (10.6%, p = 0.01) and increasing peak isometric tension (3.5 times, p = 0.001). Effects on the M responses were inhibited by propranolol (10(-6) M) (P). ACTH did not significantly modify action potential E or M parameters during cholinergic receptor antagonism or alpha-adrenergic receptor antagonism. Existence of a specific ACTH receptor was demonstrated using 125I radioiodinated ACTH 1-24. Significant binding of 125I-ACTH to AT was observed. Intracellular C-AMP levels were also measured in AT using radioimmunoassay. Tissues were exposed to 125mU/ml ACTH 1-39 plus combinations of norepinephrine (10(-6) M) (NE) and P. ACTH alone did not elevate intracellular C-AMP levels. NE increased C-AMP levels were not further increased by ACTH. Exposure to antagonist returned elevated C-AMP levels to control values. In conclusion (1) ACTH augments the NE induced M positive inotropism of the beta adrenergic receptor system. (2) ACTH specifically binds to AT and (3) ACTH does not utilize the C-AMP second messenger system.
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PMID:Electrophysiological and contractile responses of canine atrial tissue to adrenocorticotropin. 629 37

The responses of rat adrenal zona glomerulosa cells to stimulation by alpha-MSH and ACTH and related peptides have been studied. The major findings were that: (1) alpha-MSH stimulated corticosterone production in glomerulosa cells from from normal animals at concentrations of about 10(-10) mol/l, but other steroids, including aldosterone, were not significantly stimulated until levels of 10(-7) mol/l were used. Peptide structure-function relationships showed that in the adrenal cortex, in contrast with other systems, ACTH 4-10 had no effect and did not block the response of glomerulosa cells to alpha-MSH, bisacetyl Ser 1-alpha-MSH, (nor-valine-12)-alpha-MSH, and ACTH 1-13 amide were equipotent with alpha-MSH, while alpha-MSH 1-10 had activity but was considerably less potent. alpha-MSH 6-13, 7-13, 8-13 and lys-11-acetyl-alpha-MSH were all inactive. N-formyl-N-epsilon-benzyloxycarbonyl alpha-MSH stimulated only at 10(-6) mol/l. (2) Normalised alpha-MSH dose-response curves for aldosterone production in glomerulosa cells from normal rats, and corticosterone in inner zone cells were coincident. In glomerulosa cells, prior sodium depletion shifts the dose-response curve for aldosterone to the left, indicating a more sensitive response, and for corticosterone to the right. Bromocriptine treatment (which depresses the level of alpha-MSH in circulating plasma) and metoclopramide (which enhances it) respectively increased and decreased the sensitivity of the response of corticosterone to alpha-MSH in subsequently incubated glomerulosa cells, but had no effect on aldosterone. (3) In contrast, normalised ACTH stimulated dose-response curves for glomerulosa corticosterone and aldosterone, and for fasciculata corticosterone production were all coincident, and were unaffected by sodium depletion, or by metoclopramide or bromocriptine pretreatment. (4) Cyclic-AMP production by glomerulosa cells was stimulated by alpha-MSH only at levels of in excess of 10(-5) mol/l, five orders of magnitude greater than required to produce significant corticosterone stimulation. Under cyclic-AMP stimulation, the normalised responses of glomerulosa corticosterone and aldosterone, and of inner zone corticosterone were all coincident. The data suggest that alpha-MSH at low concentrations (less than 10(-7) mol/l) interacts with a glomerulosa cell receptor which is distinct from the ACTH receptor but interacts with the ACTH receptor at concentrations greater than 10(-'5) mol/l. Corticosterone production is stimulated by alpha-MSH in cells from normal animals at concentrations within the normal range for circulating plasma (approximately 3 X 10(-10) mol/l), while aldosterone is stimulated by similar concentrations of alpha-MSH in cells from sodium depleted animals. The effects of sodium depletion are not modulated through changes in plasma alpha-MSH levels. At low concentrations alpha-MSH stimulation of glomerulosa cells is unlikely to be modulated by cyclic-AMP as second messenger.
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PMID:alpha-MSH and zona glomerulosa function in the rat. 631 Feb 42

We have produced and characterized lines of transgenic mice expressing a fusion gene composed of the pituitary expression-specific promoter region of the POMC gene, driving the herpes simplex viral-1 thymidine kinase. Adult mice were treated with the antiherpes agent ganciclovir at 70 mg/kg body weight (ip, twice daily for 10-12 days). Approximately 98% of the pituitary intermediate lobe melanotropes and anterior lobe corticotropes were ablated as determined by immunocytochemistry and RIA specific for the POMC-derived peptides, ACTH, beta-endorophin, and alpha-MSH. The number of lactotropes, somatotropes, thyrotropes, and gonadotropes was not altered compared with controls, indicating that in the adult pituitary, POMC products are not required to maintain the distribution of cell types. As expected, plasma corticosterone levels were substantially decreased after POMC cell ablation. In situ hybridization studies showed that the mouse ACTH receptor was expressed uniformly throughout the adrenal cortex, and RNase protection assays revealed that the ACTH receptor mRNA decreased after pituitary POMC cell ablation. Additionally, RNase protection assays showed that pituitary POMC cell ablation resulted in the decrease of adrenal p450c11 beta transcripts while p450c11AS (aldosterone synthase) mRNA levels remained constant. These data demonstrate differential regulation of steroid pathway-specific enzymes by POMC products. Our results also suggest that the thymidine kinase cell obliteration technique may not be dependent on cell division as a prerequisite for cytotoxicity, thus supporting the idea that targeted molecular ablation using cell- and tissue-specific promoter sequences to drive viral thymidine kinase expression can be refined further to study other nonmitotic cells.
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PMID:Targeted ablation of pituitary pre-proopiomelanocortin cells by herpes simplex virus-1 thymidine kinase differentially regulates mRNAs encoding the adrenocorticotropin receptor and aldosterone synthase in the mouse adrenal gland. 747 75

A polymerase chain reaction-generated mouse ACTH-R probe was used to screen a mouse genomic library, and a clone of 13kb containing the entire coding sequence was isolated. The coding sequence shows 84% homology with the human gene at the DNA level and encodes a peptide with 89% homology to the human ACTH-R. This gene is expressed as a major transcript of 1.8kb in the mouse adrenal gland. The gene was expressed in HeLa cells and cAMP production in response to either ACTH or alpha-MSH was measured. cAMP increased in an ACTH dose dependent manner suggesting an EC50 of 7 x 10(-10)M ACTH. alpha-MSH was without effect on this receptor. In conclusion we have cloned a mouse ACTH receptor gene and demonstrated for the first time its expression and functional effect in HeLa cells.
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PMID:Cloning, characterization and expression of a functional mouse ACTH receptor. 762 30

The cloning of the melanocyte-stimulating hormone (MSH) and adrenocorticotropic hormone (ACTH) receptors (MC1-R and MC2-R, respectively) recently has led to the identification of three additional melanocortin receptors, MC3-R, MC4-R, and MC5-R. The MC2 receptor primarily recognizes only ACTH peptides, but the other four receptors all recognize alpha-melanocyte-stimulating hormone (alpha-MSH) and potent alpha-MSH agonists such as [Nle4,D-Phe7]alpha-MSH-NH2 and Ac-Nle4-c[Asp5,D-Phe7,Lys10]alpha-MSH-(4-10)-NH2 as well as ACTH. The absence of any known physiological role for these new receptors, expressed both in the brain (MC3-R and MC4-R) and throughout a number of peripheral tissues (MC5-R), has necessitated as search for potent and receptor selective agonists and antagonists. We report here that analogues of the superpotent cyclic agonist analogue Ac-Nle4-c[Asp5,D-Phe7, Lys10]alpha-MSH-(4-10)-NH2, in which a bulky aromatic amino acid is substituted in the 7-position, can produce potent and selective antagonists for melanocortin receptors. Thus, the D-p-iodophenylalanine7-containing analogue Ac-Nle4-c[Asp5,D-Phe(pI)7,Lys10]alpha-MSH-(4-10)-NH2 is a potent antagonist (pA2 = 10.3) in the classical frog skin (Rana pipiens) assay (MC1-R), as is the D-2'-naphthylalanine7 (D-Nal(2)7)-containing analogue Ac-Nle4-c[Asp5,D-Nal(2)7,Lys10]alpha-MSH-(4-10)-NH2 (pA2 > 10.3). Interestingly, the D-p-chloro- and D-p-fluorophenylalanine7-containing analogues lacked antagonist activities at all melanotropin receptors, and both exhibited full agonist potency in the frog skin assay. The activity of these analogues also was examined at four mammalian melanocortin receptors. Interestingly, Ac-Nle4-c[Asp5,(D-Nal(2)7,Lys10] alpha-MSH-(4-10)-NH2 was found to be a potent antagonist of the MC4-R (pA2 = 9.3) with minimal agonist activity, a less potent antagonist of the MC3-R (pA2 = 8.3) with minimal agonist activity, and a full agonist of the MC1 and MC5 receptors. Surprisingly, Nle4-c[Asp5,D-Phe(pI)7,Lys10]alpha-MSH was found to be a potent agonist at the cloned human MC1-R (EC50 = 0.055 nM) and mouse MC1-R (EC50 = 0.19 nM) but had potent antagonist activities at the human MC4-R (pA2 = 9.7) and human MC3-R (pA2 = 8.3) with significant partial agonist activities (EC50 = 0.57 and 0.68 nM, respectively) as well. Thus, highly potent and receptor selective antagonist analogues can arise from substitution of the D-Phe7 residue with a bulky aromatic amino acid. These analogues can be used to help determine the functional roles of these receptors.
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PMID:Cyclic lactam alpha-melanotropin analogues of Ac-Nle4-cyclo[Asp5, D-Phe7,Lys10] alpha-melanocyte-stimulating hormone-(4-10)-NH2 with bulky aromatic amino acids at position 7 show high antagonist potency and selectivity at specific melanocortin receptors. 765 32

Human genes for an adrenocorticotropin (ACTH) receptor and a melanocyte-stimulating hormone (MSH) receptor, and a mouse gene for a MSH receptor have been cloned recently. They constitute a family of receptors for peptides derived from proopiomelanocortin. The ACTH receptor mRNA and the MSH receptor mRNA were expressed only in the adrenal and melanocytes, respectively. Thereafter, three novel receptor genes for melanocortins were molecularly cloned and were expressed exclusively in the brain but not in the adrenal or melanocytes. It has remained unknown how these receptors are differentially expressed in specialized cell type. An adrenocortical cell line of mouse origin, Y-1, is to date the sole cell line which shows responsiveness to ACTH resulting in the induction of steroids. For analysis of the transcriptional regulation of ACTH receptor in Y-1 cells, I have isolated the mouse ACTH receptor gene. A 914 bp DNA fragment of the human ACTH receptor gene was amplified by polymerase chain reaction and used as a probe. Eight positive clones were obtained by screening 10(6) phage clones of a mouse genomic library under the condition of low stringency. One phage clone, lambda mCTR8 which gave the most intense hybridization signal was analyzed. It contained an approximately 12 kb insert. By comparing it with the previously reported human ACTH receptor gene and bovine ACTH receptor cDNA, the mouse homologue is intron-less in its coding region, and has a potential to encode for a 296-amino-acid polypeptide which possesses 88.9% and 78.7% identities to the human and bovine ACTH receptors, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Molecular cloning and functional expression of a mouse adrenocorticotropin receptor gene]. 777 78

Studies on neuroendocrine hormone receptor have been hampered by low numbers and concentrations of receptors found within and outside the neuroendocrine system. The complementary peptide approach is particularly useful for dealing with this problem and has been used to characterize lymphoid receptors for arginine vasopressin (AVP), corticotropin (ACTH), substance P, and opioid peptides. A nonapeptide derived by reading of the complementary DNA strand of the bovine AVP gene in the 3' to 5' direction specifically blocks the AVP helper signal for interferon-gamma production by mouse T lymphocytes. Antibodies to 3'-5' AVP-binding peptide bound to cells, and the binding was inhibited by excess AVP. Thus, binding of anti-3'-5'AVP-binding peptide antibodies to the AVP receptor was specific. The complementary peptide approach has also been used to produce antibodies specific for the ACTH receptor complex. Complementary peptides to ACTH derived by reading in either the 5' to 3' or 3' to 5' direction were able to bind to ACTH. Monospecific antibodies to the ACTH (1-24) complementary peptide caused an ACTH-like steroidogenic response of cultured mouse adrenal cells, presumably by binding to the ACTH receptor, and binding was specifically inhibited by ACTH. The ACTH receptor complex from solubilized adrenal cells was shown to consist of four subunits with M(r) 83,000, 64,000, 52,000, and 22,000. The 83,000 and 52,000 M(r) subunits are disulfide linked and noncovalently associated with the other subunits, with binding of labeled ACTH localized to the 83,000 M(r) subunit. Similarly, a complementary peptide was shown to bind directly to substance P in a saturable and dose-dependent manner.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Complementary peptides as probes to explore neuropeptide receptors on lymphocytes. 787 40

Corticotropin (ACTH) regulates glucocorticoid production through specific receptors on the adrenal cortex. Analysis of the ACTH receptor mRNA in human adrenal has revealed the presence of five transcripts ranging from 1.8 to 11 kilobases (kb). Characterization of the 5'-untranslated regions (UTRs) of the ACTH receptor mRNA demonstrated the presence of one major initiation site of transcription 177 bp away from the ATG codon. Analysis of this 5' sequence showed a perfect alignment with the previously described genomic sequence until position -128 bp from the ATG. The upstream 49-bp sequence was divergent, suggesting the occurrence of a splicing and indicating the presence of an intronic sequence in the UTRs, as well as the presence of an upstream exon containing this 49-bp sequence and located at least 1.8 kb away from the exon encoding the protein.
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PMID:Characterization of the transcription start site of the ACTH receptor gene: presence of an intronic sequence in the 5'-flanking region. 789

Using cultured human fetal adrenal cells, we have investigated the basal secretion of cortisol and dehydroepiandrosterone sulfate (DHAS) and the effect of corticotropin (ACTH), angiotensin-II (A-II) and transforming growth factor beta 1 (TGF beta 1) on the secretion of these steroids and on the mRNA levels of ACTH receptor (ACTHR), cytochrome P-450scc (cholesterol side-chain cleavage), P450 17 alpha (17 alpha-hydroxylase/17-20 lyase) and 3 beta-HSD (3 beta-hydroxysteroid dehydrogenase). The basal DHAS/cortisol ratio declined progressively between 12.5 and 21 weeks. ACTH treatment enhanced the secretion of cortisol and to a lesser extent that of DHAS, and increased the steroidogenic response to an acute stimulation with ACTH. These changes were associated with increased mRNA levels of ACTHR and of the steroidogenic enzymes. A-II treatment also increased the secretion of both DHAS and cortisol, but less than ACTH, enhanced the responsiveness to ACTH and increased ACTHR, P450scc and P450 17 alpha mRNA levels. In contrast, TGF beta 1 alone or together with ACTH decreased DHAS secretion, but not cortisol secretion. Moreover, TGF beta 1 had no effect on ACTHR and P450scc mRNA levels, decreased by about 50% the mRNA levels of P450 17 alpha both in the absence or presence of ACTH, but enhanced the stimulatory effects of ACTH on 3 beta-HSD mRNA. These results, along with those previously reported, suggest that both A-II and TGF beta may play a role in fetal adrenal function. In addition, they show that the effects of both peptides are qualitatively different from, even sometimes opposite to, those previously reported in bovine and ovine adrenal cells.
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PMID:Regulation of corticotropin and steroidogenic enzyme mRNAs in human fetal adrenal cells by corticotropin, angiotensin-II and transforming growth factor beta 1. 789 1

This report examines the basis for adrenocorticotropin (ACTH) resistance in two mutant clones (Y6 and OS3) derived from the ACTH-responsive Y1 mouse adrenocortical tumor cell line. These two mutants were originally characterized by their failure to respond to ACTH with increased adenylyl cyclase activity and as a consequence were resistant to the steroidogenic effects of the hormone. We now demonstrate that ACTH resistance in the Y6 and OS3 mutants results from the failure to express the gene encoding the ACTH receptor. Whereas parental Y1 cells express ACTH receptor transcripts at low levels and are stimulated by ACTH or 8-bromo-cAMP to increase the accumulation of ACTH receptor transcripts approximately twofold, the Y6 and OS3 mutants do not express receptor transcripts either in the presence or absence of 8-bromo-cAMP. The gene encoding the ACTH receptor appears to be present in the Y6 and OS3 mutants, as determined by Southern blot hybridization analysis. Moreover, in the Y6 mutant the ACTH receptor gene appears to be silenced by a modification that is reversed following the growth of the cells as tumors in mice. Clonal isolates of Y6 cells grown as tumors recover the ability to express ACTH receptor transcripts at low but detectable levels and acquire the ability to respond to ACTH with increased adenylyl cyclase activity. Finally, Y6 and OS3 cells transformed with a gene encoding the mouse beta 2-adrenergic receptor respond to the beta-adrenergic agonist, isoproterenol, in a manner that is indistinguishable from the similarly transformed parent Y1 cell line. These latter results demonstrate the functional integrity of the adenylyl cyclase system in the ACTH-resistant mutants and indicate that the failure to express ACTH receptor transcripts limits the responsiveness of these clones.
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PMID:Adrenocorticotropin-resistant mutants of the Y1 adrenal cell line fail to express the adrenocorticotropin receptor. 789 93


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