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: EC:4.6.1.1 (adenylate cyclase)
19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The synthesis and purification of several analogues of the melanotropins with amino acid substitutions at the tyrosine-2 and methionine-4(7) positions are reported. The compounds synthesized included [4-norleucine]-alpha-MSH, [7-norleucine]-beta p-MSH, [2-3',5'-diiodotyrosine]-alpha-MSH, [2-D-tyrosine]-alpha-MSH, and [2-phenylalanine,4-norleucine]-alpha-MSH. The biological activities of these derivatives were measured and compared on normal melanocytes (frog skins) and on transformed melanocytes (mouse melanoma adenylate cyclase), over the entire dose-response range. All compounds tested were full agonists in both assay systems but varied considerably in potency. The relative potencies in the frog skin assay (alpha-MSH = 1.0) were as follows: [Nle7]-beta p-MSH (5.2) > [Nle4]-alpha-MSH (2.3) > alpha-MSH (1.0) > [Phe2,Nle4]-alpha-MSH (0.80) > beta p-MSH (0.55) > [I2-Tyr2]-alpha-MSH (0.12) > [D-Tyr2]-alpha-MSH (0.04). The relative potencies in the melanoma adenylate cyclase system were [Nle7]-beta p-MSH (4.2) > beta p-MSH (2.2) > [Nle4]-alpha-MSH (2.0) > alpha-MSH (1.0) approximately equal to [Phe2,Nle4]-alpha-MSH (0.9) > [I2-Tyr2]-alpha-MSH (0.40) > [D-Tyr2]-alpha-MSH (0.20). There appears to be some differences in structural specificity at the melanotropin receptors of the two cell systems.
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PMID:Synthesis and structure-function studies of melanocyte stimulating hormone analogues modified in the 2 and 4(7) positions: comparison of activities on frog skin melanophores and melanoma adenylate cyclase. 745 98

A new member of the G protein-coupled receptor superfamily has been isolated from an ovine genomic library with a probe generated by the application of the PCR technique, using cDNA synthesized on a mRNA template isolated from the ovine pars tuberalis. This genomic clone encodes a novel receptor of 325 amino acids with seven transmembrane domains. These domains share homology with other members of this family, but the best homology is with the recently cloned human MC-1 (50% in the transmembrane domains) and MC-3 (69% in the transmembrane domains) MSH receptors and the human ACTH (42% in the transmembrane domains) receptor. When this receptor was expressed in Cos7 cells, it was able to bind a potent analogue of alpha-MSH, [Nle4,D-Phe7]-alpha-MSH (NDP-MSH), with high affinity. This binding could be displaced by pro-opiomelanocortin-derived and related peptides, with the order of potency NDP-MSH > alpha-MSH = ACTH > beta-MSH and with no effect of gamma-MSH, delta-MSH or beta-endorphin. The expressed receptor was demonstrated to be functionally coupled to the adenylate cyclase second messenger pathway, with alpha-MSH, beta-MSH and ACTH stimulating cyclic AMP production. The amount of the mRNA for this receptor was found to be very low. The tissue distribution of this receptor could only be observed using the reverse transcription-PCR technique and the receptor was found to be present in a number of somatic tissues. These data indicate that this is a new and distinct member of the melanocortin receptor family.
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PMID:Cloning and expression of a new member of the melanocyte-stimulating hormone receptor family. 806 Apr 85

The combined action of cholera toxin (CT)-dependent activation of the adenylate cyclase signaling pathway, stimulation of protein kinase C, and activation of the tyrosine kinase activity of cell surface receptors and proto-oncogene products, have been shown to stimulate melanocyte proliferation. However, natural factors responsible for the optimal stimulation of normal human melanocyte growth, either isolated or co-cultured with keratinocytes, remain largely unknown. alpha MSH (alpha melanocyte stimulating hormone) has previously been shown to bind to murine and human melanoma cells and to stimulate their adenylate cyclase and tyrosinase activity. In contrast, very little is known about the presence and function of alpha MSH receptors in normal human melanocytes. We now report that alpha MSH: (i) binds to normal human melanocytes through a single class of high-affinity receptors; (ii) does not induce per se melanocytes to enter the S-phase of the cell cycle; (iii) does indeed stimulate melanocyte proliferation in a dose-dependent fashion; but its stimulatory effect requires bFGF and/or the activation of protein kinase C.
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PMID:Alpha melanocyte stimulating hormone (alpha MSH) stimulates normal human melanocyte growth by binding to high-affinity receptors. 822 96

The MSH receptor belongs to a unique class of G-protein-coupled receptors, in which calcium ions control the binding affinity of MSH by a yet unknown mechanism. Possible involvement of a calcium-binding protein [e.g. calmodulin (CaM)] in the regulation of MSH receptor activity has been studied in the M2R mouse melanoma cell line. In this study, we tested the inhibitory effects of a group of calmodulin-binding peptides (CBPs) on MSH receptor activities in intact M2R cells and membrane preparations derived from them. We also report here on stimulatory effects of CBPs on cAMP production in M2R cells that could not be produced in other cell lines lacking MSH receptors. This group of CBPs includes synthetic peptides comprising the CaM-binding domains of Ca2+/CaM-dependent enzymes, cytotoxic venom peptides, and peptide hormones that have been reported to directly interact with CaM. The results show that CBPs, at micromolar concentrations, inhibit MSH binding and consequent adenylate cyclase stimulation in a specific and concentration-dependent manner, but have no effect on adenylate cyclase stimulation by prostaglandin E1. On the other hand, when MSH was omitted and forskolin (0.5-1 microM) was added instead, CBPs had the opposite effect on cAMP production, stimulating it in M2R cells, but not in other cell types tested. Thus, these peptides can be considered as antagonists of MSH receptor and partial agonists of M2R adenylate cyclase. In contrast to MSH, the stimulatory effects of CBPs were unaffected by EGTA, suggesting a Ca(2+)-independent action of these peptides. Using phospholipid vesicles and M2R cells, we recently showed that CBP activity in M2R cells may include direct partition into the lipid bilayer of the cell membrane, permitting interaction with hydrophobic lipid-inserted domains of components of the signal transducing machinery. Based on these findings, we suggest that the mechanism of action of CBPs in the M2R cells includes two major components: 1) interaction with the cell surface membrane and penetration into the lipid milieu, and 2) interaction with exposed or lipid-embedded protein epitopes intrinsically associated with the MSH-receptor system, thereby affecting the MSH receptor cascade.
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PMID:Calmodulin-binding peptides interfere with melanocyte-stimulating hormone receptor activity and stimulate adenosine 3',5'-monophosphate production in M2R mouse melanoma cells. 827 31

We have examined the mechanism of homologous regulation of MSH receptor binding and receptor-mediated adenylate cyclase activation in three human and two mouse melanoma cell lines. Pretreatment with alpha-MSH resulted in a time- and dose-dependent up-regulation of MSH receptors in human D10 and 205 melanoma cells whereas in human HBL and in mouse B16-F1 and Cloudman S91 cells alpha-MSH induced receptor down-regulation. Up-regulation of receptors was maximal after a 24-h incubation period and an alpha-MSH concentration of 100 nM (EC50 = 2.4 nM). The increase in alpha-MSH binding was independent of adenylate cyclase activation and protein synthesis and appeared to be caused by recruitment of spare receptors. The structural requirements of the peptide for triggering this process differed from those found in receptor-binding analyses. Receptor down-regulation was maximal after 12 h and hence more rapid than up-regulation. In B16-F1 cells, 10 nM alpha-MSH caused the disappearance of 85-90% of the MSH receptors, the EC50 of 0.23 nM lying exactly between that for alpha-MSH-induced melanogenesis (0.027 nM) and the dissociation constant of receptor binding (1.31 nM). Down-regulation in B16-F1 cells appears to be the consequence of receptor internalization following MSH binding and seems to be initiated during an early step in MSH signalling, preceding the activation of adenylate cyclase and the cAMP signal. Receptor up- and down-regulation were not accompanied by an alteration in affinity to alpha-MSH, as demonstrated by Scatchard analysis of the binding curves.
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PMID:Homologous regulation of the MSH receptor in melanoma cells. 838 55

The regulation of adenylate cyclase activity by adrenocorticotropin/alpha-melanocyte-stimulating hormone (ACTH/MSH)-like peptides was investigated in rat brain slices using a superfusion method. Adenylate cyclase activity was concentration-dependently increased by ACTH-(1-24), alpha-MSH (EC50 values 16 and 6 nM, respectively), and [Nle4,D-Phe7]alpha-MSH (EC50 value 1.6 nM), in the presence of forskolin (1 microM, optimal concentration). 1-9-Dideoxyforskolin did not augment the response of adenylate cyclase to ACTH-(1-24). Various peptide fragments were tested for their ability to enhance [3H]cyclic AMP production. [Nle4,D-Phe7]alpha-MSH increased [3H]cyclic AMP formation with a maximal effect of 30% and was more potent than ACTH-(1-24), ACTH-(1-16)-NH2, alpha-MSH, ACTH-(1-13)-NH2, [MetO4]alpha-MSH, [MetO2(4),D-Lys8,Phe9]ACTH-(4-9), ACTH-(7-16)-NH2, ACTH-(1-10), and ACTH-(11-24), in order of potency. This structure-activity relationship resembles that found for the previously described peptide-induced display of excessive grooming. ACTH-(1-24) stimulated adenylate cyclase activity in both striatal (maximal effect, approximately 20%) and septal slices (maximal effect, approximately 40%), but not in hippocampal or cortical slices. Lesioning of the dopaminergic projections to the striatum did not result in a diminished effect of [Nle4,D-Phe7]alpha-MSH on [3H]cyclic AMP accumulation, which indicates that the ACTH/MSH receptor-stimulated adenylate cyclase is not located on striatal dopaminergic terminals. ACTH-(1-24) did not affect the dopamine D1 or D2 receptor-mediated modulation of adenylate cyclase activity.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Adrenocorticotropin/alpha-melanocyte-stimulating hormone (ACTH/MSH)-like peptides modulate adenylate cyclase activity in rat brain slices: evidence for an ACTH/MSH receptor-coupled mechanism. 838 34

Alpha-Melanocyte-stimulating hormone (alpha-MSH) is a proopiomelanocortin (POMC)-derived peptide, which is produced in the pituitary and at other sites including the skin. It has numerous effects and in the skin has a pigmentary action through the activation of the melanocortin-1 (MC-1) receptor, which is expressed by melanocytes. Recent evidence suggests that the related POMC peptides such as adrenocorticotrophin (ACTH), which is the precursor of alpha-MSH, is also an agonist at the MC-1 receptor. By using immunocytochemistry, we confirmed the presence of alpha-MSH in human skin where staining was evident in keratinocytes and especially strong in melanocytes and possibly Langerhans cells. ACTH was also present and tended to show the strongest reaction in differentiated keratinocytes. Immunostaining was also observed for the prohormone convertases, PC1 and PC2, which are involved in the formation of ACTH and its cleavage to alpha-MSH, respectively. The amounts of immunoreactive ACTH exceeded those of alpha-MSH. Using HPLC we identified for the first time the presence of ACTH1-39, ACTH1-17, ACTH1-10, acetylated ACTH1-10, alpha-MSH, and desacetyl alpha-MSH in epidermis and in cultured keratinocytes. The ability of these peptides to activate the human MC-1 receptor was examined in HEK 293 cells that had been transfected with the receptor. All peptides increased adenylate cyclase in these cells with the following order of potency: ACTH1-17 > alpha-MSH > ACTH1-39 > desacetyl alpha-MSH > acetylated ACTH1-10 > ACTH1-10. ACTH1-17 also increased the dendricity and melanin content of cultured human melanocytes indicating that the peptide was able to activate MC-1 receptors when present in their normal location. However, as found with alpha-MSH, not all cultures were responsive and, as we have previously suggested, we suspect that this was the result of changes at the MC-1 receptor. Nevertheless, it would appear that ACTH peptides can serve as natural ligands of the MC-1 receptor on human melanocytes and their presence in the skin suggests that, together with alpha-MSH, they may have a role in the regulation of human melanocytes.
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PMID:Characterisation of ACTH peptides in human skin and their activation of the melanocortin-1 receptor. 935 24

Alpha-melanocyte-stimulating hormone (alpha-MSH) is a tridecapeptide found mainly in the brain, pituitary, and circulation. It inhibits most forms of inflammation by a mechanism that is not known. As most types of inflammation require activation of NF-kappa B, we investigated the effect of alpha-MSH on the activation of this transcription factor by a wide variety of inflammatory stimuli. Electrophoretic mobility shift assay showed that alpha-MSH completely abolished TNF-mediated NF-kappa B activation in a dose- and time-dependent manner. It also suppressed NF-kappa B activation induced by LPS, okadaic acid, and ceramide. The effect was specific, as the activation of the transcription factor activating protein-1 by TNF was unaffected. Western blot analysis revealed that TNF-dependent degradation of the inhibitory subunit of NF-kappa B, I kappa B alpha, and nuclear translocation of the p65 subunit of NF-kappa B were also inhibited. This correlated with suppression of NF-kappa B-dependent reporter gene expression induced by TNF. The inhibitory effect of alpha-MSH appeared to be mediated through generation of cAMP, as inhibitors of adenylate cyclase and of protein kinase A reversed its inhibitory effect. Similarly, addition of membrane-permeable dibutyryl cAMP, like alpha-MSH, suppressed TNF-induced NF-kappa B activation. Overall, our results suggest that alpha-MSH suppresses NF-kappa B activated by various inflammatory agents and that this mechanism probably contributes to its anti-inflammatory effects.
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PMID:Alpha-melanocyte-stimulating hormone inhibits the nuclear transcription factor NF-kappa B activation induced by various inflammatory agents. 974 48

We have previously reported that neuropeptide alpha-melanocyte stimulating hormone (alpha-MSH) successfully inhibited Matrigel invasion and haptotactic migration of B16-BL6 melanoma cells towards both fibronectin and laminin without affecting their growth. In the present study, we investigated the inhibitory mechanism of tumor cell motility by alpha-MSH. Alpha-MSH significantly blocked the autocrine motility factor (AMF)-enhanced cell motility. However, alpha-MSH did neither prevent the secretion of AMF from B16-BL6 cells nor alter the expression level of AMF receptor (gp78). On the other hand, alpha-MSH induced the secretion of the motility inhibitory factor(s) from B16-BL6 cells in a concentration- and time-dependent manner. The induction of the motility inhibitor(s) was proportional to increasing levels of intracellular cAMP induced by alpha-MSH as well as forskolin, and the activity was abolished by an adenylate cyclase inhibitor, 2',5'-dideoxyadenosine (DDA). The motility-inhibiting activity in conditioned medium (CM) from alpha-MSH-treated B16-BL6 cells was found to have a m.w. below 3 kDa after fractionation. This activity was abolished by boiling but insensitive to trypsin. The treatment of tumor cells with cycloheximide reduced the activity in alpha-MSH-stimulated CM. Our results suggest that alpha-MSH inhibited the motility of B16-BL6 cells through induction of autocrine factor(s).
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PMID:Induction of autocrine factor inhibiting cell motility from murine B16-BL6 melanoma cells by alpha-melanocyte stimulating hormone. 1007 23

Melanocortins are known to be involved in the regulation of feeding behavior. These hormones mediate their effects through G-protein-coupled receptors by stimulating adenylate cyclase. In this study we describe the functional response of melanocortin 4 receptor (MC4R) and melanocortin 3 receptor (MC3R) in HEK 293T cells, by using a luciferase reporter gene under the transcriptional control of a cAMP-responsive element (CRE) as a monitor of intracellular cAMP levels and cAMP-regulated gene expression. We were able to show that MC4R and MC3R expressed in the human cell line HEK 293T stimulate transcription induced by stimulation with different analogs of alpha-melanocyte-stimulating hormone (alpha-MSH) at different levels. In our assay of CRE-mediated gene transcription activity, alpha-MSH-ND was the most efficient alpha-MSH analog for MC4R whereas NDP-MSH was the most efficient for MC3R. Changing the His6 residue of alpha-MSH-ND to Gln or Lys markedly decreased CRE-mediated luciferase activity for MC3R compared with MC4R. On analysis by modeling the receptor-ligand complex by NMR, [Gln6]alpha-MSH-ND and [Lys6]alpha-MSH-ND showed different conformational interactions between MC3R and MC4R. Furthermore, the maximum coupling efficiency of MC4R and MC3R to G proteins was different; MC4R showed only 30-50% of the maximum activity induced by MC3R. In total, our results suggest that a differential receptor-ligand interaction is involved and that the relative interactions of MC3R and MC4R with G protein are possibly quantitatively and qualitatively different.
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PMID:Differential regulation of cAMP-mediated gene transcription and ligand selectivity by MC3R and MC4R melanocortin receptors. 1116 97


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