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)

Murine melanoma cells treated with the melanocyte-stimulating hormone (MSH) family of peptides undergo differentiation characterized by enhanced melanogenesis and altered morphology. These effects are mediated via the adenylate cyclase-cAMP pathway leading to activation of protein kinase A (PKA). We have discovered that inhibition of a post-translational modification of chromatin proteins, viz. poly(ADP-ribosylation), also induces melanogenesis and differentiation in these cells. A range of competitive inhibitors (benzamide and its derivatives) of the nuclear enzyme poly(ADP-ribose) polymerase (PADPRP; EC 2.4.2.30) was utilized, and their ability to induce melanogenesis reflected their potency as PADPRP inhibitors. These compounds induced melanogenesis at low doses (20 microM-2 mM) which did not affect cell growth or viability. Induction of melanogenesis was not attributable to inhibition of cyclic nucleotide phosphodiesterase by these compounds. MSH treatment caused a transient rise in cAMP levels (up to 200-fold by 5 min and returning to near basal levels by 5 h). It also stimulated PKA activity up to 5-fold, and the temporal kinetics of this activation mirrored the changes in cAMP levels. In comparison, the PADPRP inhibitors had no effect on either of these processes. These data constitute a novel demonstration of a cAMP-independent mechanism for the induction of melanoma cell differentiation, including melanogenesis.
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PMID:Murine melanoma cell differentiation and melanogenesis induced by poly(ADP-ribose) polymerase inhibitors. 132 52

The authors examined the effect of topical application of agents known to increase cyclic nucleotide levels on tear secretion by accessory lacrimal gland tissue in their rabbit model for keratoconjunctivitis sicca (KCS). Tear secretion was studied by changes in tear film osmolarity and tear volume caused by application of the agents relative to application of isotonic buffer solution alone. A decrease in tear film osmolarity or increase in tear volume was interpreted as an increase in tear secretion. Irritative stimulation was distinguished from pharmacologic stimulation by the prior use of topical proparacaine. The following agents significantly decreased tear film osmolarity and increased tear volume: vasoactive intestinal peptide (2 X 10(-8) to 2 X 10(-6) M); three pro-opiomelanocortin fragments alpha-, beta-, and gamma-melanocyte stimulating hormone at 10(-4), 10(-3), and 10(-3) M, respectively; the permeable cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) analogs 8-Br cAMP (0.3-3.0 X 10(-3) M) and 8-Br cGMP (1.0-10.0 X 10(-3) M); and the cyclic nucleotide phosphodiesterase inhibitor 1-isobutyl-3-methyl xanthine (0.3-3.0 X 10(-3) M). Forskolin (2 X 10(-4) M), which activates the catalytic subunits of adenyl cyclase, increased tear volume significantly. Secretin, adrenocorticotropic hormone, and pilocarpine were ineffective. The authors conclude that agents that increase either cAMP or cGMP levels pharmacologically stimulated tear secretion when applied topically to rabbit eyes with surgically induced KCS.
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PMID:Stimulation of tear secretion by topical agents that increase cyclic nucleotide levels. 236 69

Acetylation at the alpha-amino terminal is a common post-translational modification of many peptides and proteins. In the case of the potent opiate peptide beta-endorphin, alpha-N-acetylation is a known physiological modification that abolishes opiate activity. Since there are no known receptors for alpha-N-acetyl-beta-endorphin, we have studied the association of this peptide with calmodulin, a calcium-dependent protein that binds a variety of peptides, phenothiazines, and enzymes, as a model system for studying acetylated endorphin-protein interactions. Association of the acetylated peptide with calmodulin was demonstrated by cross-linking with bis(sulfosuccinimidyl)suberate; like beta-endorphin, adducts containing 1 mol and 2 mol of acetylated peptide per mole calmodulin were formed. Some of the bound peptides are evidently in relatively close proximity to each other since, in the presence of amidated (i.e., lysine-blocked) calmodulin, cross-linking yielded peptide dimers. The acetylated peptide exhibited no appreciable helicity in aqueous solution, but in trifluoroethanol (TFE) considerable helicity was formed. Also, a mixture of acetylated peptide and calmodulin was characterized by a circular dichroic spectrum indicative of induced helicity. Empirical prediction rules, applied earlier to beta-endorphin, suggest that residues 14-24 exhibit alpha-helix potential. This segment has the potential of forming an amphipathic helix; this structural unit is believed to be important in calmodulin binding. The acetylated peptide was capable of inhibiting the calmodulin-mediated stimulation of cyclic nucleotide phosphodiesterase (EC 3.1.4.17) activity with an effective dose for 50% inhibition of about 3 microM; this inhibitory effect was demonstrated using both an enzyme-enriched preparation as well as highly purified enzyme. Thus, acetylation at the alpha-amino terminal of beta-endorphin, although abolishing opiate activity, does not interfere with the binding to calmodulin. Indeed, beta-endorphin and the alpha-N-acetylated peptide behave very similarly with respect to calmodulin association.
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PMID:Interaction of alpha-N-Acetyl-beta-endorphin and calmodulin. 285 97

The 31-residue neuropeptide, beta-endorphin, inhibits the calmodulin-dependent activity of activatable cyclic nucleotide phosphodiesterase. We have shown that the amino terminal portion of the peptide, which includes the sequence conferring opiate activity, is not required for inhibitory potency and, furthermore, that solution complexes of the peptides and calmodulin render calmodulin functionally inactive in terms of cyclic nucleotide phosphodiesterase activation. An amino terminal deletion peptide of human beta-endorphin (beta-endorphin 13-31), synthesized using solid phase methods, was shown to interact with calmodulin by cross-linking with bis(sulfosuccinimidyl)suberate and by a gel permeation chromatographic technique. Results from the latter approach, using peptide concentrations of 2-100 microM, demonstrated Ca2+-dependent equilibrium binding with an apparent stoichiometry of approximately 4 mol of peptide/mol of calmodulin and half-maximal binding at 15-20 microM.
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PMID:Binding of a synthetic beta-endorphin peptide to calmodulin. 293 15

The 31-residue neuropeptide porcine beta-endorphin was shown to inhibit the Ca2+-dependent calmodulin activation of highly purified bovine brain cyclic nucleotide phosphodiesterase (3',5'-cyclic AMP 5'-nucleotidohydrolase, EC 3.1.4.17). Using a series of deletion peptides, the minimal inhibitory peptide sequence was found to correspond to beta-endorphin residues 14-25, confirming previously reported results for crude enzyme preparations. A correlation was found between the relative inhibitory potency of a particular beta-endorphin deletion peptide and the efficacy of cross-linking that peptide to calmodulin with bis(sulfosuccinimidyl) suberate, strongly implicating peptide binding to calmodulin as the mechanism of the observed inhibition. We found that relatively modest concentrations of chlorpromazine significantly reduced the efficiency of cross-linking beta-endorphin 14-31 to calmodulin. Chlorpromazine-Sepharose affinity chromatography of peptide/calmodulin adducts showed that a significant portion of the cross-linked beta-endorphin 14-31/calmodulin complex (stoichiometry of 1 mol/mol) retained the ability to interact with the immobilized phenothiazine in a Ca2+-dependent and calmodulin-displaceable manner. In contrast, the 2:1 (peptide:protein) product exhibited no affinity for the immobilized phenothiazine. The use of this affinity chromatographic step allowed preparation of homogeneous populations of both 1:1 and 2:1 beta-endorphin 13-31/calmodulin complexes and assessment of their functional characteristics. Equilibrium binding studies with chlorpromazine revealed that the covalent attachment of one peptide molecule to calmodulin perturbed all phases of Ca2+-dependent drug binding, but the adduct still bound significant quantities of chlorpromazine. The 2:1 complex, however, showed little detectable binding of the phenothiazine.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Functional properties of covalent beta-endorphin peptide/calmodulin complexes. Chlorpromazine binding and phosphodiesterase activation. 300 46

It is known that the 31-residue neuropeptide beta-endorphin inhibits the calcium-dependent, calmodulin-mediated stimulation of cyclic nucleotide phosphodiesterase activity. The results of this study demonstrate that a non-opiate, synthetic amino terminal deletion peptide, des-(1-13), of human beta-endorphin is also capable of inhibiting the stimulated enzymic activity, but not the basal activity. This inhibition occurs with the same efficacy as the intact 31-residue peptide. Thus, the amino terminal region of beta-endorphin, which is responsible for opiate activity, does not appear to contribute to the calmodulin interaction. Circular dichroic spectroscopy of des-(1-13) beta-endorphin, calmodulin, and mixtures of the two shows that the ellipticity at 221 nm was more negative in the peptide-protein mixture than could be accounted for on the basis of simple additivity of the peptide and calmodulin. This spectral change implies enhanced alpha-helicity concomitant with the peptide-protein association. Helix formation may occur in the peptide since this sequence has the potential to form an amphipathic helix.
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PMID:des-(1-13) human beta-endorphin interacts with calmodulin. 631 32

The inhibition of the calmodulin-mediated stimulation of bovine brain cyclic nucleotide phosphodiesterase activity (3':5'-cyclic adenosine monophosphate 5'-nucleotidohydrolase, EC 3.1.4.17) by the 31-residue opiate peptide beta-endorphin has been investigated. Using conditions in which porcine brain calmodulin (6 nM) is limiting (i.e., to give a 3-fold, Ca2+-dependent stimulation of enzymic activity toward cyclic guanosine monophosphate), the domain of beta-endorphin responsible for the inhibition was mapped by using a series of deletion peptides. beta-Endorphin exhibited an ED50 of several micromolar under the conditions employed, and several amino-terminal deletion peptides were essentially as inhibitory as the parent peptide. Methionine enkephalin and various carboxy-terminal deletion peptides had no demonstrable effect at concentrations of 100-200 microM. Peptides 1-25 and 1-27 (C' fragment) inhibited the calmodulin-dependent activity of phosphodiesterase, but higher concentrations were required than of beta-endorphin. Studies using combined amino- and carboxy-terminal deletion peptides demonstrate that peptide 14-25 was the shortest peptide examined that was capable of inhibiting calmodulin stimulation of phosphodiesterase activity under the conditions used. There was no evidence to indicate that the amino-terminal region comprising residues 1-13 of beta-endorphin contributes to the measured inhibition of calmodulin-stimulated enzymic activity. The circular dichroic spectra of calmodulin, beta-endorphin, and mixtures of the two were obtained, and the ellipticity of the peptide-protein mixtures at 221 nm exceeded that expected by assuming simple additivity. This finding is consistent with a direct interaction of beta-endorphin with calmodulin which seems to lead to enhanced helicity of one or both components.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Identification of beta-endorphin residues 14-25 as a region involved in the inhibition of calmodulin-stimulated phosphodiesterase activity. 631 22

The effect of several opioids: methadone, etorphine, beta-endorphin and D-ala2met enkephalin on Ca++/calmodulin stimulation of enzyme activities either in pure solution (cyclic nucleotide phosphodiesterase) or in striatal membranes (protein kinases in synaptic membranes) were compared to see if a direct opioid/calmodulin interaction could eliminate the stimulation of enzyme activity as part of the mechanism by which opioids alter ion flow and neurotransmitter release. In other experiments, in which endogenous phosphorylation of proteins in striatal synaptic membranes was altered by opioid treatments, the possibility of restoring protein kinase activity to normal levels in the membrane preparation by supplementation with calmodulin at optimal Ca++ concentration was examined. Some opioids (methadone and D-ala2met enkephalin) did not inhibit calmodulin-stimulated phosphodiesterase, which suggests that they were not able to bind to calmodulin. In addition, it was not possible to restore decreases in protein kinase activity to normal levels by adding calmodulin to the assay in the presence of optimal Ca++. We conclude that a direct binding of opioids to calmodulin is not a general mechanism of opioid action, although the binding may participate in the action of some neuropeptides, including beta-endorphin.
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PMID:Is a calmodulin-opiopeptide interaction related to the mechanism of opioid action? 631 23