Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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 mouse adrenocortical cell line Y1, that expresses ACTH receptors (MC2R), was used to probe the binding of ACTH and MSH peptides by using radio-labelled ACTH (1-39). The Y1 cells were found to bind [125I]-labelled ACTH (1-39) with high affinity (Kd approximately 130 pM). However, none of the melanocortin peptides NDP-MSH, alpha-MSH, beta-MSH or gamma 1-MSH could compete with the binding of the labelled ACTH(1-39). When other MC receptor subtype DNAs (MC1, MC3 and MC4) were transfected into the Y1 cells, characteristic binding of the [125I]NDP-MSH appeared for each of the receptor subtype, but no specific binding was present in non-transfected cells. This is the first report clearly demonstrating that the ACTH receptor binds only ACTH, but not other melanocortin peptides.
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PMID:Major pharmacological distinction of the ACTH receptor from other melanocortin receptors. 876 13

Stimulation of steroidogenesis in the adrenal cortex is a major physiological action of adrenocorticotropic hormone (ACTH). This action is presumed to be mediated by the ACTH receptor and is functionally connected with the hypothalamus-pituitary-adrenal axis. To gain information concerning the distribution of the ACTH receptor in this axis, we examined mRNA for the ACTH receptor in the adrenal gland, pituitary and hypothalamus of the mouse, by using in situ hybridization. The Y-1 mouse adrenal tumour cell line was also examined. The specific hybridization signal for ACTH receptor mRNA was uniformly distributed in the Y-1 cells, although the level of expression was low. The adrenal cortex showed a strong signal for the ACTH receptor mRNA in both the zona fasciculata and the zona glomerulosa, sites that are involved in the mediation of the action of ACTH on the synthesis and release of glucocorticoids and aldosterone. In the zona reticularis of the cortex, a small number of cells showed positive hybridization signals. Moreover, a few scattered cells were positive in the adrenal medulla. In contrast, the hybridization results for both the hypothalamus and the pituitary proved to be negative. These results indicate that the mouse ACTH receptor is a peripheral receptor that is exclusively located in the adrenal gland.
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PMID:Localization of ACTH receptor mRNA by in situ hybridization in mouse adrenal gland. 878 Dec 13

As a step for analysis of the transcriptional regulation of the adrenocorticotropin (ACTH) receptor gene, I have made an attempt to obtain a full length cDNA and determined the genomic organization of the mouse ACTH receptor. Using the 5'-RACE (rapid amplification of cDNA ends) method, a 374bp sequence upstream of the translation start codon ATG of the receptor was obtained. By comparison of the 374bp sequence with the 1.8kb genomic sequence within the phage clone, lambda mCTR8, containing the mouse ACTH receptor coding region as described previously, a 95bp sequence of the 5'-RACE-generated cDNA was found to locate from the position of -1 to -95 from the ATG, and a 113bp sequence of the 5'-RACE-generated cDNA was found in the genomic sequence approximately 1.6kb upstream of the ATG. Because of the absence of a 166bp sequence, -209 to -374, in lambda mCTR8, further screening of a mouse genomic library was performed. By analysis of two positive clones, a 109bp and a 57bp sequence, -266 to -374 and -209 to -265, respectively, were located approximately 6.0kb away from each other in the phage clones which were not overlapped with lambda mCTR8. The 3'non-coding region of the mouse ACTH receptor cDNA obtained by 3'-RACE method was contiguous to the coding region by comparing it with the 1.4kb genomic sequence downstream of the ATG. The polyadenylation signal AATAAA was located at the position of 1291 from the ATG. Taken together, the mouse ACTH receptor gene consists of at least 4 exons and three of the exons encoded 5'-untranslated sequences. Moreover, two mRNAs in the presence and absence of the 57bp putative exon 2 generated by alternative splicing were determined by reverse transcription/polymerase chain reaction between putative exon 1 and 4. Finally, the longest cDNA of this gene determined from this experiment was 1707bp while northern analysis revealed approximately 1.8kb mRNA in mouse adrenal gland. It awaits further investigation to clarify the significance of 5'-untranslated non-coding exons and alternative splicing in this receptor gene.
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PMID:[The genomic organization of the mouse adrenocorticotropin receptor]. 893 9

[Nle4, DPhe7]-alpha-MSH (NDP-MSH), a highly potent analogue of alpha-melanocyte-stimulating hormone (alpha-MSH), possesses nanomolar efficacies at all the melanocortin receptor subtypes except the MC2R. Evaluation of the melanocortin "message" sequence of [Nle4, DPhe7]-alpha-MSH was performed on the human melanocortin receptor subtypes designated hMC1, hMC3R, hMC4R, and hMC5R. Tetrapeptides and tripeptides were stereochemically modified to explore topochemical preferences at these receptors and to identify lead peptides possessing agonist activity and subtype selectivity. Four peptides were discovered to only bind to the hMC1 and hMC4 receptor subtypes. The tetrapeptide Ac-His-DPhe-Arg-Trp-NH2 (1) possessed 0.6 microM binding affinity at the hMC1R, 1.2 microM binding affinity at the hMC4R, and agonist activity at both receptors. The tripeptides Ac-DPhe-Arg-Trp-NH2 (6) and Ac-DPhe-Arg-DTrp-NH2 (7) possessed 2.0 and 9.1 microM binding affinities, respectively, only at the hMC4R, and both compounds effected agonist activity. The tetrapeptide Ac-His-Phe-Arg-DTrp-NH2 (4) possessed 6.3 microM affinity and full agonist activity at the hMC1R, while only binding 7% at the hMC3R, 36% at the hMC4R, and 11% at the hMC5R at a maximal concentration of 10 microM. These data demonstrate that the His-Phe-Arg-Trp message sequence of the melanocortin peptides does not bind and stimulate each melanocortin receptor in a similar fashion, as previously hypothesized. Additionally, this study identified the simplest structural agonists for the hMC1R and hMC4R receptors reported to date.
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PMID:Discovery of prototype peptidomimetic agonists at the human melanocortin receptors MC1R and MC4R. 921 31

Melanocortins, melanocyte-stimulating hormones (MSH) and adrenocorticotropic hormone (ACTH) are homologous natural peptides derived from pro-opiomelanocortin (POMC). Recent breakthroughs in melanocortin receptor (MCR) biology are relevant to neuroimmunomodulation because melanocortins are known to modulate fever, inflammation and immunity, by acting both on peripheral targets and within the brain. During fever, endogenous melanocortins exert antipyretic effects by acting on MCR located within the brain, suggesting a protective counterregulatory role of the central melanocortin system. MCR are also found in melanocytic cells and adrenal cortical cells, the classical targets for alpha-MSH and ACTH, respectively, in myelogenous and lymphoid tissues, and in various endocrine and exocrine glands, adipocytes, and in autonomic ganglia. In the CNS, MCR are prominently distributed in close proximity to the terminal fields of melanocortinergic neurons that innervate neuroendocrine and autonomic motor nuclei as well as other subcortical brain regions important in neuroendocrine and autonomic regulation, sensory processing and various aspects of behavior. Furthermore, the presence of MCR in circumventricular organs of the brain provides direct access of systemic melanocortin hormones to central MCR. Together, these attributes provide an anatomical basis for bidirectional MCR-mediated communication between brain and periphery. A group of five G-protein-associated MCR subtypes, each of which is positively coupled to adenylate cyclase, has been identified. Among these, the adrenal ACTH receptor (MC2-R) is selectively activated by ACTH. In contrast, the other MCR subtypes (MC1-R, MC3-R, MC4-R, MC5-R) recognize a common group of ligands that includes various forms of MSH as well as ACTH; nevertheless they do exhibit important differences in ligand selectivity. MCR concentrations and MCR mRNA levels are influenced by availability of cognate ligands, by drugs, and by pathological stimuli. Two types of endogenous MCR antagonist proteins have been discovered: agouti protein and the corticostatins. Agouti protein dramatically alters coat color in mammals by antagonizing melanocytic MC1-R. Moreover, spontaneous dominant mutations of the agouti gene in several strains of mice lead to its ubiquitous overexpression and produces not only yellow coat color, but also obesity and insulin resistance, perhaps as a result of its antagonism of other MCR subtypes. The recent emergence of synthetic MCR antagonists, and the feasibility of molecular approaches for targeted inactivation of individual MCR subtypes, should facilitate elucidation of the roles and mechanisms of neuroimmunomodulation by endogenous melanocortins, and the determination of whether selective pharmacological targeting of MCR may ultimately have therapeutic utility.
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PMID:Receptor biology of the melanocortins, a family of neuroimmunomodulatory peptides. 921 48

Familial glucocorticoid deficiency (FGD) has long been recognised as a clinical entity, but molecular studies have so far been performed in only a few individuals. We describe a girl born to consanguineous Pakistani parents with clinical and biochemical features of FGD who is homozygous for the R146H mutation of the adrenocorticotropic hormone (ACTH) receptor gene. This mutation creates a new restriction enzyme site in the ACTH receptor gene, allowing accurate characterisation of the mutation without DNA sequencing. Our patient is the third child reported to be homozygous for the R146H mutation. Interestingly, she has a tall stature, a clinical finding reported in several children who have ACTH insufficiency and mutations of the ACTH receptor gene. We suggest that mutation analysis of the ACTH receptor gene be considered in children with clinical features of FGD and tall stature.
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PMID:ACTH receptor mutation in a girl with familial glucocorticoid deficiency. 955 Mar 64

The recent cloning of a family of melanocortin receptors (MC-R) has identified five distinct G protein- and adenylate cyclase-coupled receptors. The MC2-receptor (MC2-R) preferentially binds ACTH. It is expressed in the adrenal cortex and is hence considered to be the ACTH receptor. The MC5-receptor (MC5-R) binds ACTH and alpha-MSH and is more widely expressed. The aim of this work was to study the sites of MC5-R expression in the bovine adrenal cortex and to compare the regulation of the expression of MC2-R and MC5-R in bovine adrenocortical cells in primary culture. Analysis of the expression of MC5-R was obtained by RT-PCR, using total RNA purified from glomerulosa and fasciculata zones of bovine adrenocortical tissue. MC5-R expression could be detected in RNA from the glomerulosa zone but was undetectable in the fasciculata zone. In bovine adrenocortical cells in culture, ACTH stimulates MC5-R expression in the glomerulosa and fasciculata cells. A DNA fragment, was obtained using primers based on the bovine ACTH receptor (MC2-R) sequence. This fragment was detected in RNA from the two zones. The probe was used to quantify MC2-R by Ribonuclease Protection assay and we observed that MC2-R mRNA is 3.6-fold more abundant in glomerulosa than in fasciculata-reticularis cells.
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PMID:Expression of ACTH receptors (MC2-R and MC5-R) in the glomerulosa and the fasciculata-reticularis zones of bovine adrenal cortex. 988 20

Previous work with growing chickens (Gallus gallus domesticus) indicates that transient dietary protein restriction induces long-term enhancement of adrenal steroidogenic function in response to adrenocorticotropin (ACTH). The present study investigated two possible cellular functions mediating this enhanced response: (a) ACTH signal transduction and dissemination and (b) short-loop feedback inhibition of ACTH-induced corticosterone production by exogenous corticosterone. Cockerels (2 weeks old) were fed isocaloric synthetic diets containing either 20% (control) or 8% (restriction) soy protein for 4 weeks. Adrenal glands were processed for the isolation of adrenal steroidogenic cells nearly devoid of chromaffin cells ( approximately 90% adrenal steroidogenic cells). Results of experiments to assess signal transduction and dissemination indicated that protein restriction selectively enhanced ACTH-induced corticosterone production mediated by the cyclic AMP (cAMP)-dependent pathway. In addition, protein restriction substantially counteracted exogenous corticosterone-dependent inhibition of acute ACTH-induced corticosterone production (by 40.7% vs control). The proximal portion of the cAMP pathway seemed most affected by this stressor. Protein-restricted cells exhibited enhanced homologous sensitization to ACTH (136% greater than that of control cells) which appeared to be localized at a step(s) prior to or at the formation to cAMP. Also, maximal ACTH-induced cAMP production and sensitivity to ACTH in terms of cAMP production by protein-restricted cells were, respectively, 2.2 and 15.8 times those of control cells. However, variable results were obtained from other experiments designed to pinpoint the altered early steps in ACTH-transmembranous signaling. For example, with intact cells, cAMP responses to cholera toxin (CT) and forskolin (FSK) did not corroborate the results suggesting an augmentation of ACTH-signal transduction induced by protein restriction. Furthermore, basal and stimulatable (by ACTH, CT, FSK, and NaF) adenylyl cyclase activities from membranes from protein-restricted cells were, respectively, 47.2 and 40.2% less than those from control cells (normalized to 10(7) cell equivalents of crude membranes). Collectively, these findings suggest that protein restriction stress potentiates ACTH-induced corticosterone secretion by chicken adrenal steroidogenic cells in at least two ways: (1) on the proximal end, by modulating unknown factors which enhance cellular sensitivity to ACTH, ACTH receptor-adenylyl cyclase coupling, and adenylyl cyclase activity, and (2) on the distal end, by suppressing end-product corticosterone negative feedback, thus facilitating an increase in net corticosterone secretion.
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PMID:Dietary protein restriction stress in the domestic fowl (Gallus gallus domesticus) alters adrenocorticotropin-transmembranous signaling and corticosterone negative feedback in adrenal steroidogenic cells. 1008 28

Eight crossbred sows were selected for the present study (n = 4 vaginal delivery and n = 4 Caesarian section [C-section]). Gestation length did not differ between vaginal delivery and C-section pigs (113.6 +/- .1 and 113.2 +/- .3 d, respectively; P > .16). Blood and tissue samples from 38 pigs were collected at birth. All remaining pigs were sustained with vaginal-delivery sows until 2 wk of age (n = 39). At 2 wk of age, remaining pigs were catheterized for blood sample collection to assess pituitary-adrenal responsiveness to an injection of corticotropin-releasing hormone (CRH; 10 microg/kg). Blood samples were collected at -30, -15, 0, 5, 10, 20, 40, 60, and 90 min; pigs received CRH or saline at time 0. Pigs were killed and tissue samples were collected immediately following the last blood sample. Serum concentrations of ACTH and cortisol (CS) were measured. Total RNA was isolated from the pituitary and adrenal glands to evaluate gene expression for mRNA specific for pro-opiomelanocortin (POMC) and for the ACTH receptor. Centrifuged clot:blood ratio was reduced in the C-section pigs at birth (P < .001) and at 2 wk of age (P < .043), compared with the vaginally delivered pigs. Basal serum concentration of ACTH was greater in C-section than in vaginally delivered pigs at birth (P = .01) but did not differ at 2 wk of age (P = .42). Basal serum concentration of CS was not different at birth (P = .86) but was greater in C-section pigs than in vaginally delivered pigs at 2 wk of age (P < .04). Serum concentration of ACTH was not different (P > .99) between the two groups of pigs following the CRH challenge. However, serum concentration of CS was greater (P < .05) in C-section pigs following the CRH challenge. Expression of ACTH receptor mRNA tended to be greater in C-section pigs at birth (P < .063) and at 2 wk of age (P < .016). There was no difference in POMC mRNA between treatments (P > .73); however, there was a developmental increase (P < .001) from birth to 2 wk of age. These data indicate that the birth process plays an important role in postnatal function of the hypothalamic-pituitary-adrenal axis in young pigs.
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PMID:Birth by caesarian section alters postnatal function of the hypothalamic-pituitary-adrenal axis in young pigs. 1022 72

Among the five members of the melanocortin receptor (MC-R) family, MC2 and MC5 are expressed in peripheral tissues. The receptor MC2 (ACTH receptor) almost exclusively expressed in the adrenal cortex whereas MC5-R is expressed in several organs including the adrenal cortex. Both receptors bind ACTH and activate adenylate cyclase. The aim of this work was to study the spatial distribution of MC5-R among the different zones of the bovine adrenal cortex and to analyze the regulation of its expression by its own ligands, ACTH and alpha-MSH and by angiotensin II (AII). Using semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) analysis and RNase protection assay, MC5-R was detected only in the glomerulosa zone whereas MC2-R was present in both glomerulosa and fasciculata zones of adult adrenal cortex. Treatments by ACTH, alpha-MSH, or AII increased the MC5-R mRNA level in glomerulosa cells by factors 7, 5, and 4.5, respectively. However, although potentially regulated by hormones, MC5-R is expressed at a level at least 100 times less than MC2-R, suggesting that MC5-R expression might only be at trace levels in grown adults, but could be much higher during embryogenesis.
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PMID:Expression and regulation of melanocortin receptor-5 (MC5-R) in the bovine adrenal cortex. 1068 56


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