UNIPROT:P01189 - FACTA Search

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Query: UNIPROT:P01189 (beta-endorphin)
21,003 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mouse agouti protein is a paracrine signaling molecule that has previously been demonstrated to be an antagonist of melanocortin action at several cloned rodent and human melanocortin receptors. In this study we report the effects of agouti-signaling protein (ASIP), the human homolog of mouse agouti, on the action of alpha-MSH or ACTH at the five known human melanocortin receptor subtypes (hMCR 1-5). When stably expressed in L cells (hMC1R, hMC3R, hMC4R, hMC5R) or in the adrenocortical cell line OS3 (hMC1R, hMC2R, hMC4R), purified recombinant ASIP inhibits the generation of cAMP stimulated by alpha-MSH (hMC1R, hMC3R, hMC4R, hMC5R) or by ACTH (hMC2R). However, dose-response and Schild analysis indicated that the degree of ASIP inhibition varied significantly among the receptor subtypes; ASIP is a potent inhibitor of the hMC1R, hMC2R, and hMC4R, but has relatively weak effects at the hMC3R and hMC5R. These analyses also indicated that the apparent mechanism of ASIP antagonism varied among receptor subtypes, with characteristics consistent with competitive antagonism observed only at the hMC1R, and more complex behavior observed at the other receptors. ASIP inhibition at these latter receptors, nonetheless, can be classified as surmountable (hMC3R, hMC4R and hMC5R) or nonsurmountable (hMC2R). Recombinant ASIP also inhibited binding of radiolabeled melanocortins, [125I-Nle4, D-Phe7] alpha-MSH and [125I-Phe2, Nle4]ACTH 1-24, to the hMCR 1-5 receptors, with a relative efficacy that paralleled the ability of ASIP to inhibit cAMP accumulation at the hMC1R, hMC2R, hMC3R, and hMC4R. These results provide new insight into the biochemical mechanism of ASIP action and suggest that ASIP may play an important role in modulating melanocortin signaling in humans.
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PMID:Effects of recombinant agouti-signaling protein on melanocortin action. 905 74

We have previously reported that melatonin was an effective lightening agonist in the teleost Synbranchus marmoratus, the amphibians Rana pipiens and Bufo ictericus, and in the lizard Anolis carolinensis. The hormone, previously applied to the preparations, effectively inhibited alpha-MSH darkening activity in a dose-independent manner, and was also able to reverse MSH-induced darkening. We presently describe the inhibitory effect of the indoleamine on the murine melanoma cell proliferation. Interestingly, the hormone also stimulated tyrosinase activity, with a correlated increase in melanin content. We also demonstrate that in a diverse lizard species, Urosaurus ornatus, the indoleamine was totally ineffective. The competitive MSH antagonistic activity of H-His-D-Arg-Ala-Trp-D-Phe-Lys-NH2 has been demonstrated previously in R. pipiens and U. ornatus. Herein, its inhibitory activity is also reported in another lizard species, A. carolinensis. However, this MSH analogue was inactive in S. marmoratus, and in murine melanoma cells. On the other hand, the 7 thru 10 alpha-MSH fragment, Ac-Phe-Arg-Trp-Gly-NH2, although ineffective in S. marmoratus and R. pipiens, was an alpha-MSH antagonist in A. carolinensis. Surprisingly, in the melanoma cell line, the MSH fragment exhibited no agonist or antagonist activity, but dramatically potentiated the MSH-induced increase in tyrosinase activity. These data might suggest that the fragment is participating either in the process of facilitation or in positive cooperativity. The present results, taken together with our previously reported data, demonstrate a major interspecies diversity of the MC1 subtype of melanocortin receptor, and point out the relevance of the membrane microenvironment for the final receptor configuration.
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PMID:Comparative biological activities of alpha-MSH antagonists in vertebrate pigment cells. 907 3

Bacterial infection causes fever, an adaptive but potentially self-destructive response, in the host. Also activated are counterregulatory systems such as the pituitary-adrenal axis. Antipyretic roles have also been postulated for certain endogenous central neuropeptides, including the melanocortins (alpha-MSH-related peptides). To test the hypothesis that endogenous central melanocortins have antipyretic effects mediated by central melanocortin receptors (MCRs), we determined the effect of intracerebroventricular injection of a synthetic MCR antagonist, Ac-Nle4,c-[Asp5,DNal(2')7,Lys10]alpha-MSH(4-10)-NH2 (SHU-9119) in endotoxin-challenged rats. The efficacy and specificity of SHU-9119 as an MCR antagonist in the rat was first validated in vitro and in vivo. In vitro, in heterologous cells expressing either rat MC3-R or MC4-R, the major MCR subtypes expressed in brain, SHU-9119 showed no intrinsic agonism, but it inhibited alpha-MSH-induced cAMP accumulation (IC50 = 0.48 +/- 0.19 and 0.41 +/- 0.28 nM, respectively) and [125I]-[Nle4,DPhe7]-alpha-MSH binding (IC50 = 1.0 +/- 0.1 and 0.9 +/- 0.3 nM, respectively). In vivo, exogenous alpha-MSH (180 pmol) inhibited fever in rats when administered intracerebroventricularly 30 min after Escherichia coli lipopolysaccharide (LPS) (25 microg/kg, i.p.). When co-injected with alpha-MSH, SHU-9119 (168 pmol, i.c.v.) prevented the antipyretic action of exogenous alpha-MSH. In contrast, neither alpha-MSH nor SHU-9119, alone or in combination, affected body temperatures in afebrile rats. In LPS-treated rats, intracerebroventricular injection of SHU-9119 significantly increased fever, whereas intravenous injection of the same dose of SHU-9119 had no effect. Neither intracerebroventricular nor intravenous SHU-9119 significantly affected LPS-stimulated plasma ACTH or corticosterone levels. The results indicate that endogenous central melanocortins exert an antipyretic influence during fever by acting on MCRs located within the brain, independent of any modulation of the activity of the pituitary-adrenal axis.
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PMID:Antipyretic role of endogenous melanocortins mediated by central melanocortin receptors during endotoxin-induced fever. 909 67

1. We investigated the effects of [Nle4,D-Phe7]alpha-melanocyte-stimulating hormone (NDP-MSH), adrenocorticotropin-(1-24) (ACTH-(1-24)) and gamma 2-MSH, three melanocortins with different agonist selectivity for the five cloned melanocortin receptors, on blood pressure and heart rate in conscious, freely moving rats following intravenous administration. 2. As was previously found by other investigators as well as by us gamma 2-MSH, a peptide suggested to be an agonist with selectivity for the melanocortin MC3 receptor, caused a dose-dependent, short lasting pressor response in combination with a tachycardia. Despite the fact that NDP-MSH is a potent agonist of various melanocortin receptor subtypes, among which the melanocortin MC1 receptor, it did not affect blood pressure or heart rate, when administered i.v. in doses of up to 1000 nmol kg-1. 3. ACTH-(1-24) caused a dose-dependent decrease in blood pressure in combination with a dose-dependent increase in heart rate in a dose-range from 15 to 500 nmol kg-1. The cardiovascular effects of ACTH-(1-24) were independent of the presence of the adrenals. 4. Pretreatment with ACTH-(1-24) caused a pronounced, dose-dependent parallel shift to the right of the dose-response curve for the pressor and tachycardiac effects of gamma 2-MSH. The antagonistic effect of ACTH-(1-24) was already apparent following a dose of this peptide as low as 10 nmol kg-1, which when given alone had no intrinsic hypotensive activity. 5. These results form further support for the notion that it is not via activation of one of the as yet cloned melanocortin receptors that gamma-MSH-like peptides increase blood pressure and heart rate. The cardiovascular effects of ACTH-(1-24) seem not to be mediated by the adrenal melanocortin MC3 receptors, for which ACTH-(1-24) is a selective agonist, or by adrenal catecholamines. 6. There appears to be a functional antagonism between ACTH-(1-24) and gamma 2-MSH, two melanocortins derived from a common precursor, with respect to their effect on blood pressure and heart rate. Whether this antagonism plays a (patho)physiological role remains to be shown.
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PMID:Different cardiovascular profiles of three melanocortins in conscious rats; evidence for antagonism between gamma 2-MSH and ACTH-(1-24). 911 79

Adrenocorticotropic hormone (ACTH) and alpha-melanocyte stimulating hormone (alpha-MSH) are centrally acting melanocortin peptides with numerous reported functions, including induction of excessive grooming and antipyresis, among others. Also reported is a role for melanocortins in aspects of opiate action. Although early work examined the effects of ACTH and MSH on opiate-induced behaviors, further progress has been limited. Recently, however, advances in the identification and characterization of melanocortin receptor (MC-R) subtypes have provided novel tools with which to study interactions between melanocortins and addiction. The present review discusses the effects of ACTH and MSH on opiate-induced behaviors and relates these findings to more recent reports on the regulation of melanocortin systems by exogenous opiates. Emerging from these data is the possibility that melanocortin receptor activation, specifically at the MC4-R subtype, may act to antagonize certain properties of exogenous opiates, including perhaps addiction.
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PMID:Melanocortins and opiate addiction. 920 Jun 63

[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

The human melanocortin 5 receptor (hMC5R) in the melanocortin receptor family has been identified as the receptor with low affinity towards alpha-MSH. Here we show that the glutamine at position 235 and arginine at the position 272 in the hMC5R are contributing to the low affinity of this receptor. Glutamine235 and arginine272 in hMC5R were mutated to lysine (Q235K) and cysteine (R272C), respectively, residues which are conserved at these positions in other melanocortin receptor subtypes. Upon these mutations affinity of alpha-MSH for hMC5R was increased 10-fold for Q235K and 690-fold for R272C mutants, respectively. The results explain the unusually low affinity of the hMC5R to the melanocortic ligands and suggest the importance of these conserved residues in maintaining the high affinity form of melanocortin receptors.
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PMID:Glutamine235 and arginine272 in human melanocortin 5 receptor determines its low affinity to MSH. 924 Apr 66

A phage display system for the selection of peptides binding to heterologously expressed human melanocortin receptor 1 on the surface of insect cells has been established. It could be shown that phage particles displaying the natural ligand alpha-melanocyte-stimulating hormone bind selectively to cells expressing this receptor and that these phages exhibit biological activity on mouse B16F1 melanoma cells. Insect cells were superior to other cell lines tested and have been used to select binders from a small library, in which critical determinants (Phe7-Arg8-Trp9) were kept, whereas the flanking regions where allowed to variate freely. One peptide displaying little similarity with native hormone was found that binds to the receptor also in its free form with an affinity of 7 nM. It showed a remarkable selectivity for this receptor, because it binds to the other melanocortin receptor subtypes with a maximum affinity of 21 microM. This is the first time phage display has been used successfully with G-protein-coupled receptors lacking an extracellular binding domain.
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PMID:Phage display selection on whole cells yields a peptide specific for melanocortin receptor 1. 934 44

Recent reports show that alpha-MSH (melanocyte-stimulating hormone) is mitogenic and melanogenic for normal human melanocytes, and that this effect is mediated through binding to the melanocortin receptor (MC1R) and activation of cAMP formation. alpha-MSH has also been shown to induce changes in cell shape in melanocytes and melanoma cells, particularly increased dendricity, suggesting a potential role for alpha-MSH in melanocyte-matrix interactions and pigment transfer through reorganization of the melanocyte actin filament cytoskeleton. In this report we show that the potent alpha-MSH analog (Nle4, D-Phe7)-alpha-MSH (NDP-MSH) induces reorganization of the actin stress fiber cytoskeleton in treated human melanocytes and that this reorganization is associated with increased adhesion to fibronectin (FN). Because most melanocyte growth factors act synergistically on melanocyte mitogenesis, we also sought to determine the effect of the melanocyte mitogen endothelin-1 (ET-1) on the melanocyte actin cytoskeleton, melanocyte adhesion, and melanocyte migration. We show that ET-1, which increases melanocyte migration on FN, has opposite effects on melanocyte adhesion to FN compared with NDP-MSH and that endothelin-1-induced actin reorganization is distinct from that observed following NDP-MSH treatment. Finally, we show that focal adhesion kinase (pp125FAK), a nonreceptor tyrosine kinase associated with focal contact formation and cell migration, is phosphorylated on tyrosine residues after treatment of melanocytes with ET-1, but not NDP-MSH. These data indicate that while alpha-MSH and ET-1 act synergistically to modulate melanocyte proliferation, they have opposite effects on melanocyte-matrix interactions.
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PMID:Alpha-melanocyte-stimulating hormone and endothelin-1 have opposing effects on melanocyte adhesion, migration, and pp125FAK phosphorylation. 941 62

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