Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P01189 (beta-endorphin)
 21,003 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In B16 melanocytes, tyrosinase activity and melanin formation are upregulated by alpha-MSH and downregulated by TGF beta1 and TNF alpha. Since TGF beta1 or TNF alpha block the differentiation programs induced by throphic hormones in other cell types, we studied tyrosinase regulation by alpha-MSH in the presence of the hypopigmenting cytokines, as well as the effects of the cytokines on several aspects of alpha-MSH signaling. TGF beta1 and TNF alpha only slightly diminished MC1 receptor gene expression, and had no effect on the intracellular levels of cAMP, or on the alpha-MSH-dependent cAMP rise. The intracellular levels of tyrosinase mRNA, protein and enzymatic activities were also upregulated by alpha-MSH in cells pretreated with TGF beta1 or TNF alpha. Therefore the cytokines do not block the response to alpha-MSH. However, the cytokine-induced inhibition of tyrosinase gene expression, protein levels and the reduction of tyrosinase intracellular half-life also occurred in the presence of alpha-MSH, indicating that the hormone does not override TGF beta1 or TNF alpha inhibition. Thus, tyrosinase activity and the rate of melanin formation in B16 melanocytes might reflect simply the balance between alpha-MSH stimulation and TGF beta1 or TNF alpha inhibition, acting by independent mechanisms.
 ...
PMID:Independent regulation of tyrosinase by the hypopigmenting cytokines TGF beta1 and TNF alpha and the melanogenic hormone alpha-MSH in B16 mouse melanocytes. 1064 3

The melanocortin receptor MC1 is expressed on melanocytes and is an important control point for melanogenesis and other responses. Alpha-MSH, which is considered to be the major ligand at the human melanocortin (MC)1 receptor (hMC1R), is produced from proopiomelanocortin (POMC) in the pituitary and in the skin by melanocytes and keratinocytes. Other POMC peptides are also produced in the skin and their concentrations exceed those of alpha-MSH by several fold. One of the most abundant is ACTH1-17. We have shown that adrenocorticotrophic hormone (ACTH)1-17 is more potent than alpha-MSH in stimulating melanogenesis in human melanocytes and unlike alpha-MSH produces a biphasic dose response curve. In this study we have examined the ability of ACTH1-17 to function as a ligand at the hMC1R. Competitive binding assays with [125I]Nle4 DPhe7 alpha-MSH as labelled ligand were carried out in HEK 293 cells transfected with the hMC1R. ACTH1-17 showed high affinity for the hMC1R with a Ki value of 0.21 +/- 0.03 nM which was slightly higher than that of 0.13 +/- 0.005 nM for alpha-MSH. ACTH1-17 was, however, more potent than alpha-MSH in increasing cAMP and IP3 production in the transfected cells. Our results demonstrate that ACTH1-17 is a potent agonist at the hMC1R. It is therefore possible that ACTH1-17, which is found in the skin in greater concentrations than alpha-MSH, has an important role in the regulation of human melanocytes and other cell types that express the hMC1R.
 ...
PMID:ACTH1-17 is a more potent agonist at the human MC1 receptor than alpha-MSH. 1064 6

alpha-MSH, has numerous actions in the skin and by activating the MC1 receptor (MC1-R) on melanocytes it stimulates melanogenesis. Rather than producing large increase in melanin production alpha-MSH acts specifically to stimulate eumelanin synthesis. Although this could be important in determining skin color and tanning there is debate as to the pigmentary significance of alpha-MSH in humans. Circulating levels of alpha-MSH are negligible and although it is produced in the skin by different cell types, including melanocytes, the major skin form is desacetyl alpha-MSH, and this is a weak agonist at MC1-R. Certain ACTH peptides, notably ACTH1-17, are more potent agonists at the MC1-R and, since their skin concentrations exceed those of alpha-MSH, they could serve as natural ligands at this receptor and regulate pigmentary responses in humans. Activation of MC1-R does, however, produce other responses in human melanocytes. Thus, alpha-MSH stimulates melanocyte dendricity and attachment to extracellular matrix proteins. It also protects melanocytes from the damaging effects of oxidative stress, and regulates their production of NO by modulating the induction of iNOS--as it does within macrophages. alpha-MSH clearly affects various aspects of melanocyte behavior and its melanogenic effects could be the consequence of a more fundamental role in the melanocyte. The precise nature of this role is unclear, but it could be part of a generic role that alpha-MSH and other POMC peptides have in skin homeostasis.
 ...
PMID:alpha-MSH and the regulation of melanocyte function. 1081 55

The skin is a known target organ for the proopiomelanocortin (POMC)-derived neuropeptides alpha-melanocyte stimulating hormone (alpha-MSH), beta-endorphin, and ACTH and also a source of these peptides. Skin expression levels of the POMC gene and POMC/corticotropin releasing hormone (CRH) peptides are not static but are determined by such factors as the physiological changes associated with hair cycle (highest in anagen phase), ultraviolet radiation (UVR) exposure, immune cytokine release, or the presence of cutaneous pathology. Among the cytokines, the proinflammatory interleukin-1 produces important upregulation of cutaneous levels of POMC mRNA, POMC peptides, and MSH receptors; UVR also stimulates expression of all the components of the CRH/POMC system including expression of the corresponding receptors. Molecular characterization of the cutaneous POMC gene shows mRNA forms similar to those found in the pituitary, which are expressed together with shorter variants. The receptors for POMC peptides expressed in the skin are functional and include MC1, MC5 and mu-opiate, although most predominant are those of the MC1 class recognizing MSH and ACTH. Receptors for CRH are also present in the skin. Because expression of, for example, the MC1 receptor is stimulated in a similar dose-dependent manner by UVR, cytokines, MSH peptides or melanin precursors, actions of the ligand peptides represent a stochastic (predictable) nonspecific response to environmental/endogenous stresses. The powerful effects of POMC peptides and probably CRH on the skin pigmentary, immune, and adnexal systems are consistent with stress-neutralizing activity addressed at maintaining skin integrity to restrict disruptions of internal homeostasis. Hence, cutaneous expression of the CRH/POMC system is highly organized, encoding mediators and receptors similar to the hypothalamic-pituitary-adrenal (HPA) axis. This CRH/POMC skin system appears to generate a function analogous to the HPA axis, that in the skin is expressed as a highly localized response which neutralizes noxious stimuli and attendant immune reactions.
 ...
PMID:Corticotropin releasing hormone and proopiomelanocortin involvement in the cutaneous response to stress. 1089 29

It is well established that melanocortic peptides, such as melanocyte-stimulating hormone (MSH) and adrenocorticotropin, induce grooming behavior. The MC3 and MC4 receptors are the MC receptors which are most abundantly expressed in the brain. gamma-MSH, a peptide with preference to the MC3 receptor, however, does not induce grooming. Recent studies have shown that MC4 receptor antagonists are very effective in inhibiting alpha-MSH induced grooming. These data have indicated that grooming behavior in rodents may be mediated by the MC4 receptor. In this study we investigated if the recently developed MC1 receptor selective agonist MS05 was able to induce grooming in comparison with alpha-MSH. The results show that MS05 is effective in inducing grooming after either intracerebroventricular or ventral tegmental area administration in rats. Central administration of either MS05 or alpha-MSH besides grooming also induced stretching, yawning, rearing and locomotion. The results indicate that the earlier hypothesis that the MC4 receptor is the main mediator of grooming behavior has to be modified. Moreover, as this behaviour does not pharmacologically correlate to the profile of any of the five cloned MC receptors, we suggest that alpha-MSH induced grooming may not primarily be mediated by any of these receptors.
 ...
PMID:Evidence that alpha-MSH induced grooming is not primarily mediated by any of the cloned melanocortin receptors. 1098 23

The melanocortin 3 and 4 receptors are G-protein-coupled receptors found in the hypothalamus with important role in regulation of the energy balance. In this study, we performed pharmacological comparison of the rat and human melancortin (MC) 3 and MC4 receptors. We transiently expressed the genes for these receptors individually in a mammalian cell line and determined the binding affinities to several MSH peptides. The results showed no major difference between the rat and human MC3 receptors while the rat MC4 receptor had higher affinity to several peptides compared with the human MC4 receptor. NDP-, alpha-, beta-, gamma-MSH, ACTH(1-24), HS014 and MTII had from 5- to 34-fold higher affinity for the rat MC4 receptor, while SHU9119, HS024 and HS028 had similar affinity for both the MC4 receptors. Pharmacological species difference have earlier been reported for the MC1 and MC5 receptors but this is the first report showing important differences between the rat and human MC4 receptors.
 ...
PMID:Pharmacological comparison of rat and human melanocortin 3 and 4 receptors in vitro. 1204 4

The melanocortin pathway is involved in the regulation of several physiological functions including skin pigmentation, steroidogenesis, obesity, energy homeostasis, and exocrine gland function. This melanocortin pathway consists of five known G-protein coupled receptors, endogenous agonists derived from the proopiomelanocortin (POMC) gene transcript, the endogenous antagonists Agouti and the Agouti-related protein (AGRP) and signals through the intracellular cAMP signal transduction pathway. The endogenous melanocortin agonists contain the putative message sequence "His-Phe-Arg-Trp," postulated to be important for melanocortin receptor molecular recognition and stimulation. Herein, we report a tetrapeptide library, based upon the template Ac-His-D-Phe-Arg-Trp-NH(2), consisting of 20 members that have been modified at the Trp(9) position (alpha-MSH numbering) and pharmacologically characterized for agonist activity at the mouse melanocortin receptors MC1R, MC3R, MC4R, and MC5R. Results from this study yielded compounds that ranged in pharmacological properties from equipotent to a loss of melanocortin receptor activity at up to 100 microM concentrations. Interestingly, modification of the Trp(9) in the tetrapeptide template at the MC1R resulted in only up to a 220-fold potency change, while at the MC4R and MC5R, up to a 9700-fold decrease in potency was observed, suggesting the MC1R is more tolerant of the modifications examined herein. The most notable results of this study include identification that the Trp(9) indole moiety in the tetrapeptide template is important for melanocortin-3 receptor agonist potency, and that this position can be used to design melanocortin ligands possessing receptor selectivity for the peripherally expressed MC1 and MC5 versus the centrally expressed MC3 and MC4 receptors. Specifically, the Ac-His-D-Phe-Arg-Tic-NH(2) and the Ac-His-D-Phe-Arg-Bip-NH(2) tetrapeptides possessed nanomolar MC1R and MC5R potency but micromolar MC3R and MC4R agonist potency. Additionally, these studies identified that substitution of the Trp amino acid with either Nal(2') or D-Nal(2') resulted in equipotent melanocortin receptor potency, suggesting that the chemically reactive Trp indole side chain may be replaced with the nonreactive Nal(2') moiety for the design of nonpeptide melanocortin receptor agonists.
 ...
PMID:Structure-activity relationships of the melanocortin tetrapeptide Ac-His-D-Phe-Arg-Trp-NH2 at the mouse melanocortin receptors. 4. Modifications at the Trp position. 1247 57

The melanocortin receptors are peptide binding G-protein coupled receptors that play a role in important physiological functions such as energy balance, inflammatory processes and several aspects of reproduction. In this study, we synthesised 11 new linear MSH analogues and tested their binding to the human MC receptors (MC1, MC3, MC4 and MC5) expressed in COS cells. Our results show that introduction of Asp in position 4 similarly affects the binding to the MC1, MC4 and MC5 receptors, but drastically lowers the binding to the MC3 receptor. Arg(5) substitution shows relatively high affinity for the MC4 receptor, while the results also give further support for specific importance of His(6) for the MC1 receptor. Introduction of Asp in position 10, mimicking gamma-MSH, decreased the affinity for the MC3 receptor in similar manner as for the MC4 receptor, suggesting that there are important differences in the binding conformation of gamma-MSH and NPD-MSH. Our results provide further information about the ligand binding requirements for each of the MC receptor subtypes, and highlights differential influence of the core residues in the MSH peptides. The data set also provides useful information for further calculations and modeling of MC receptor binders.
 ...
PMID:Subtype selective binding properties of substituted linear melanocyte stimulating hormone analogues. 1250 37

We investigated the effects of a novel melanocortin-4 (MC4) receptor antagonist,1-[(S)-2-(4-fluorophenyl)-2-(4-isopropylpiperadin-1-yl)ethyl]-4-[4-(2-methoxynaphthalen-1-yl)butyl]piperazine (MCL0129) on anxiety and depression in various rodent models. MCL0129 inhibited [(125)I][Nle(4)-D-Phe(7)]-alpha-melanocyte-stimulating hormone (alpha-MSH) binding to MC4 receptor with a K(i) value of 7.9 nM, without showing affinity for MC1 and MC3 receptors. MCL0129 at 1 microM had no apparent affinity for other receptors, transporters, and ion channels related to anxiety and depression except for a moderate affinity for the sigma(1) receptor, serotonin transporter, and alpha(1)-adrenoceptor, which means that MCL0129 is selective for the MC4 receptor. MCL0129 attenuated the alpha-MSH-increased cAMP formation in COS-1 cells expressing the MC4 receptor, whereas MCL0129 did not affect basal cAMP levels, thereby indicating that MCL0129 acts as an antagonist at the MC4 receptor. Swim stress markedly induced anxiogenic-like effects in both the light/dark exploration task in mice and the elevated plus-maze task in rats, and MCL0129 reversed the stress-induced anxiogenic-like effects. Under nonstress conditions, MCL0129 prolonged time spent in the light area in the light/dark exploration task and suppressed marble-burying behavior. MCL0129 shortened immobility time in the forced swim test and reduced the number of escape failures in inescapable shocks in the learned helplessness test, thus indicating an antidepressant potential. In contrast, MCL0129 had negligible effects on spontaneous locomotor activity, Rotarod performance, and hexobarbital-induced anesthesia. These observations indicate that MCL0129 is a potent and selective MC4 antagonist with anxiolytic- and antidepressant-like activities in various rodent models. MC4 receptor antagonists may prove effective for treating subjects with stress-related disorders such as depression and/or anxiety.
 ...
PMID:Anxiolytic-like and antidepressant-like activities of MCL0129 (1-[(S)-2-(4-fluorophenyl)-2-(4-isopropylpiperadin-1-yl)ethyl]-4-[4-(2-methoxynaphthalen-1-yl)butyl]piperazine), a novel and potent nonpeptide antagonist of the melanocortin-4 receptor. 1253 38

Seven alleles of the chicken melanocortin (MC) 1 receptor were cloned into expression vectors, expressed in mammalian cells and pharmacologically characterized. Four of the clones e(+R), e(+B&D), e(wh)/e(y), E(Rfayoumi) gave receptors to which melanocortin stimulating hormone (alpha-MSH) and NDP-MSH bound with similar IC50 values and responded to alpha-MSH by increasing intracellular cAMP levels in a dose-dependent manner. Three of the cMC1 receptors; e(b), E and E(R), did not show any specific binding to the radioligand, but were found to be constitutively active in the cAMP assay. The E and E(R) alleles are associated with black feather colour in chicken while the eb allele gives rise to brownish pigmentation. The three constitutively active receptors share a mutation of Glu to Lys in position 92. This mutation was previously found in darkly pigmented sombre mice, but constitutively active MC receptors have not previously been shown in any nonmammalian species. We also inserted the Glu to Lys mutation in the human MC1 and MC4 receptors. In contrast with the chicken clones, the hMC1-E94K receptor bound to the ligand, but was still constitutively active independently of ligand concentration. The hMC4-E100K receptor did not bind to the MSH ligand and was not constitutively active. The results indicate that the structural requirements that allow the receptor to adapt an active conformation without binding to a ligand, as a consequence of this E/K mutation, are not conserved within the MC receptors. The results are discussed in relationship to feather colour in chicken, molecular receptor structures and evolution. We suggest that properties for the 'E92K switch' mechanism may have evolved in an ancestor common to chicken and mammals and were maintained over long time periods through evolutionary pressure, probably on closely linked structural features.
 ...
PMID:Association of feather colour with constitutively active melanocortin 1 receptors in chicken. 1265 99


<< Previous 1 2 3 4 5 6 Next >>