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 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

Septal kindling was associated with an inhibition of the post hoc phosphorylation of several synaptic plasma membrane proteins of rat hippocampus. In control rats, the 32P incorporation into proteins of molecular weights 50,000, 58,000, and 60,000 was markedly stimulated by combined calcium/calmodulin, whereas in kindled animals, the response to combined calcium/calmodulin was reduced. Calcium alone, cAMP, or cGMP modulated 32P incorporation into several synaptic plasma membrane proteins but did not differentiate control from kindled tissues. Both control and kindled rats showed nonspecific inhibition of calcium/calmodulin-stimulated phosphorylation in the post hoc assay by corticotropin and by [Leu]enkephalin. The differences between control and kindled animals were most striking in hippocampus and in the amygdaloid-entorhinal area; less pronounced in cortex, basal ganglia, and brain stem; and not significant in cerebellum, a region where kindling cannot be elicited. An 8-wk period of rest after kindling did not reduce these changes, suggesting that they may be a persistent as the kindling behavior itself.
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PMID:Kindling alters the calcium/calmodulin-dependent phosphorylation of synaptic plasma membrane proteins in rat hippocampus. 632 92

The protein kinase activities endogenous to synaptic membranes prepared by an identical procedure from avian (chick) and mammalian (rat) brains were compared. Both species showed similar responses towards both protein kinase effector molecules cyclic adenosine monophosphate and Ca2+. Kapp for cyclic adenosine monophosphate-dependent protein kinase activity occurred at 0.4-0.8 microM cAMP and Kapp for Ca2+-dependent, calmodulin-requiring protein kinase activity occurred at 1-2 microM Ca2+ (free ion concentration) both in the absence or presence of calmodulin added to the reaction mixture. This suggests that endogenous calmodulin in these membranes was able to modulate the Ca2+-dependent, calmodulin requiring protein kinase activity. After EGTA-treatment of the membranes to remove endogenous Ca2+ and calmodulin, no significant response towards Ca2+ on the phosphorylation of the membrane polypeptides was measured unless exogenous calmodulin was added after which the Kapp for Ca2+ was increased to 15 microM Ca2+ (free ion concentration). There was a difference in the maximal levels of kinase activity in these membranes with chick membranes containing 57% less cyclic adenosine monophosphate-dependent protein kinase activity, but 65% more Ca2+-dependent, calmodulin-requiring protein kinase activity than the rat membranes. Similar results were determined when either low (5 microM) or high (5.8 microM) concentrations of adenosine 5'-triphosphate were added to the reaction mixtures. Besides certain species differences in the molecular weights of the resulting phosphoproteins, we observed several major differences with respect to the absence or presence of some of the phosphoproteins. Chick synaptic membranes may lack the cyclic adenosine monophosphate-requiring, microtubule-associated phosphoprotein, MAP2, one of the 2 neurospecific, cyclic adenosine monophosphate-requiring and Ca2+, calmodulin-requiring phosphoproteins (Protein Ib, although Protein Ia apparently is present), and the Ca2+-requiring, calmodulin-independent, ACTH-sensitive phosphoprotein, B50. The phenothiazines, trifluoperazine, fluphenazine and chlorpromazine were found to inhibit the Ca2+-dependent, calmodulin-requiring protein kinase activities of both the chick and rat synaptic membranes. This inhibition appeared to be specific for calmodulin because at the same concentrations the phenothiazine analogue, chlorpromazine-sulfoxide, had no effect on this activity. Also found to inhibit Ca2+-dependent calmodulin-requiring protein kinase activity were dibucaine and adrenocorticotropin. These data suggest that rat forebrain synaptic plasma membranes are activated by cyclic adenosine monophosphate
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PMID:Endogenous protein phosphorylation in chick and rat brain synaptic membranes. 666 99

Calmodulin (CaM) binding by turkey gizzard myosin light chain kinase (MLCK) causes subtle changes in the fluorescence emission and polarization excitation spectra of the enzyme. Fluorescence experiments using 9-anthroyl-choline (9AC), which competes with ATP in binding, demonstrate mutually stabilizing interactions between the CaM and ATP binding sites corresponding to delta G = -0.6 to -0.7 kcal/mol. Fluorescence titrations in the presence of 9AC or 5,5'-bis[8-(phenylamino)-1-naphthalenesulfonate] confirm the stoichiometry of 1 mol of CaM/MLCK. Phosphorylation of MLCK has no effect on either the protein fluorescence or the binding of ATP and 9AC. The dissociation constant for the MLCL-CaM complex is increased approximately 500-fold on phosphorylation. Values of Kd for the phosphorylated enzyme range from 0.5 to 1.1 microM in 0.2 N KCl, pH 7.3, 25 degrees C. We showed competition between MLCK and other CaM binding proteins and peptides by using both fluorescence and catalytic activity measurements. Competition for CaM occurs with ACTH, beta-endorphin, substance P, glucagon, poly(L-arginine), myelin basic protein, troponin I, and histone H2A. Phosphorylation of the last three proteins by the adenosine cyclic 3',5'-phosphate dependent protein kinase diminishes their ability to compete. Phosphorylation of MLCK by the protein kinase gives 0.95 +/- 0.04 and 2.2 +/- 0.4 mol of incorporated 32P in the presence and absence of CaM, respectively. These stoichiometries agree with those recently reported [Conti, M. A. & Adelstein, R. S. (1981) J. Biol. Chem. 256, 3178].
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PMID:Functional interactions between smooth muscle myosin light chain kinase and calmodulin. 689 95

The localization of calmodulin, a calcium-dependent modulator of many enzymes, was studied in rat liver, skeletal muscle, and adrenal slices. Calmodulin is found in liver cytoplasm, nucleus, and plasma membrane. Much of the cytoplasmic calmodulin is associated with glycogen particles presumably bound to enzymes involved in glycogen metabolism. Skeletal muscle calmodulin is found on the I-band, also associated with glycogen particles. Intermyofibrillar staining that is not glycogen associated is also observed. Calmodulin is localized in the cytoplasm and nucleus of adrenal cortex cells. Injection of corticotropin leads to a greatly increased localization of calmodulin in nuclei of the adrenal cortex. These observations suggest that one role of calmodulin may be the regulation of hormone effects on nuclear processes.
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PMID:Localization of calmodulin in rat tissues. 698 50

The properties of the calcium/calmodulin-dependent protein phosphatase calcineurin and its potential role in stimulus-secretion coupling were examined in AtT20 mouse pituitary corticotrope tumor cells. Protein phosphatase activity was assayed by measuring the liberation of 32P from 32P-casein, adrenocorticotropin secretion was measured by radioimmunoassay. About 60% of the total phosphatase activity was inhibited by 500 nM okadaic acid, suggesting the presence of protein phosphatases 1 and/or 2A. A further 25-30% reduction of phosphatase activity was achieved by chelating free calcium. Addition of the EF-hand protein blocker trifluoperazine or a calcineurin autoinhibitory peptide fragment markedly reduced okadaic acid resistant and calcium-dependent protein phosphatase activity indicating that calcium-dependent 32P release is largely due to calcineurin (protein phosphatase 2B). The remaining 10-15% of total activity was Mg2+ dependent and blocked by NaF, hence possibly due to protein phosphatase 2C. Calcineurin activity was inhibited by the immunosuppressants FK506 and cyclosporin A, either when added to the cell lysates or after preincubation of intact cells with the drugs for 30 min at 37 degrees C. When added to lysates, cyclosporin A inhibited calcium/calmodulin-dependent phosphatase more effectively than FK506. However, when tested on intact cells, FK506 proved 10-fold more potent than cyclosporin A. Both immunosuppressive agents enhanced the calcium-dependent release of adrenocorticotropic hormone into the medium, once more, FK506 was 10-fold more potent than cyclosporin A. Taken together, these data suggest that calcineurin is an inhibitory element in the signal transduction pathway controlling exocytotic secretion in pituitary cells that express voltage-operated calcium channels. This is in direct contrast with leukocytes where voltage-operated calcium channels are not found, and calcineurin is an important element for agonist-induced activation.
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PMID:Inhibitory role for calcineurin in stimulus-secretion coupling revealed by FK506 and cyclosporin A in pituitary corticotrope tumor cells. 768 29

Angiotensin II (AII) receptors are known to interact with two distinct guanine nucleotide binding proteins, Gq/11 and Gi, in rat adrenal glomerulosa cells to activate phospholipase C and to inhibit adenylate cyclase, respectively. However, in cultured bovine glomerulosa cells AII potentiates rather than inhibits the stimulatory effect of adrenocorticotropin (ACTH) on cAMP levels. This effect of AII was partially mimicked by phorbol 12-myristate 13-acetate (PMA) and was partially inhibited by staurosporine or depletion of protein kinase C but was unaffected by pertussis toxin treatment. No potentiation was detectable in disrupted cells or in membrane preparations. In intact glomerulosa cells, treatment with cyclosporin A or FK506 completely inhibited AII- or PMA-induced potentiation of cAMP production without affecting the response to ACTH. In COS-7 cells transfected with the rat AT1 receptor, AII caused 2-3-fold enhancement of the ACTH-induced cAMP response, an effect that was partially reproduced by PMA. These potentiating actions of AII and PMA were prevented by preincubation with cyclosporin A or FK506, and the latter effect was abolished by rapamycin. These results implicate the Ca2+- and calmodulin-dependent protein phosphatase, calcineurin, in AII-induced enhancement of adenylate cyclase activity in both adrenal glomerulosa and transfected COS-7 cells. The finding that AII enhances ACTH-stimulated production of cAMP by a second messenger-mediated mechanism that involves the participation of calcineurin reveals an additional mode of cross-talk between pathways activated by Ca(2+)-mobilizing and cAMP-generating receptors.
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PMID:Evidence for participation of calcineurin in potentiation of agonist-stimulated cyclic AMP formation by the calcium-mobilizing hormone, angiotensin II. 792 24

Membrane depolarization is a critical element of neuronal signaling. In this study, the biochemical and molecular mechanisms involved in transcriptional regulation of the corticotropin-releasing hormone (CRH) gene by depolarization were investigated. In PC-12 cells, potassium-induced membrane depolarization increased expression of a CRH-reporter construct in a cAMP-dependent manner. This synergistic activation was mediated via calcium influx, predominantly via L-type calcium channels, and calmodulin. RNase protection assays demonstrated increased levels of CRH-reporter transcripts in stably transfected cells after treatment with cAMP and potassium, with the induced transcripts initiating at the major transcription initiation site of the human CRH gene. At the genomic level, the CRH cAMP-responsive element conferred both positive cAMP and synergistic cAMP/depolarization regulation to a heterologous promoter. Additionally, DNase I protection assays demonstrated similar nuclear protein/DNA binding profiles across the cAMP-responsive element after treatment of PC-12 cells with potassium or potassium/cAMP. These results support a model in which the protein(s) binding to the cAMP-responsive element integrates signals initiated by multiple pathways (cAMP and calcium) and transmits that integrated signal to the basal transcription machinery, resulting in increased levels of gene expression.
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PMID:The cAMP-responsive element in the corticotropin-releasing hormone gene mediates transcriptional regulation by depolarization. 818 84

Synthetic calmodulin-binding (CaM-binding) peptides (CBPs) representing CaM-binding domains of Ca2+/CaM-dependent enzymes have been reported to interfere with the activity of the melanocyte-stimulating hormone (MSH) receptor function in melanoma cells [Gerst, J. E., & Salomon, Y. (1988) J. Biol. Chem. 263, 7073-7078]. We postulated that membrane lipids may play an important role in the mode of action of CBPs on cells. We therefore tested the ability of CBPs to interact with membrane bilayers. Using artificial phospholipid vesicles, or M2R melanoma cells and cell membranes derived therefrom, as models, we report here that synthetic peptides representing the CaM-binding domains of skeletal muscle myosin light chain kinase (M5) and the human erythrocyte calcium pump (C28W), as well as other CBPs, interact with lipid bilayers and cell membranes. Significant interactions of CBPs with the lipid bilayer were detected in both model systems. M5 and C28W were found to partition into the lipid bilayer of melanoma cell membranes and soybean lecithin vesicles, and surface partition constants obtained (for the liposome model) were in the range 10(3)-10(4) M-1. In addition, C28W and its N-modified NBD derivative were found to inhibit [125I]iodo-[Nle4,D-Phe7]alpha MSH binding to cultured M2R melanoma cells. These and other CBPs were also found to induce the release of cations and calcein from liposomes, suggesting that the interaction of CBPs with the lipid bilayer increases membrane permeability.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Synthetic peptides corresponding to the calmodulin-binding domains of skeletal muscle myosin light chain kinase and human erythrocyte Ca2+ pump interact with and permeabilize liposomes and cell membranes. 839 69

We studied the effect of the adenylate cyclase activator forskolin, of protein kinase C-activating phorbol esters and of prolonged preganglionic input activation on the inhibitory response of the perfused superior cervical ganglion of the cat to exogenous met-enkephalin (Met-ENK). Met-ENK inhibited, in a concentration-dependent manner, the postganglionic compound action potential evoked by cervical sympathetic trunk stimulation. The inhibition was reversible, was blocked by naloxone as well as by pertussis toxin and showed no homologous desensitization in the concentration range 0.01-10 microM. Pretreatment of the ganglion with 4 beta-phorbol 12,13-dibutyrate or 4 beta-phorbol 12,13-diacetate depressed the Met-ENK response for several hours, while pretreatment with forskolin had no effect. This action of phorbol esters was prevented by the protein kinase inhibitor H-7 but not by the calmodulin antagonist W-7 or the protein kinase A inhibitor HA 1004 and was calcium-dependent. Recovery of the response from the depression produced by phorbol esters was not affected by a protein synthesis inhibitor. A 40 Hz 20 min stimulus train to the cervical sympathetic trunk mimicked the effect of phorbol esters, depressing for several hours the inhibition produced by Met-ENK. Stimulus trains of duration shorter than 5 min or frequency lower than 5 Hz were ineffective. This effect of prolonged preganglionic stimulation occurred even when the stimulus train was delivered during complete block of nicotinic and muscarinic ganglionic transmission but was lost when the stimulus train was delivered during perfusion with calcium-free Krebs. The protein kinase inhibitor H-7 prevented the depression of the Met-ENK response by the train, while W-7 and HA 1004 had no effect. These findings suggest that, in the superior cervical ganglion of the cat, a kinase, activated by phorbol esters and inhibited by H-7, exerts a long-term control of the ganglion cell responsiveness to opiate receptor activation. A similar mechanism can be synaptically activated by a non-cholinergic transmitter, released by the preganglionic axons during prolonged, high frequency, activity.
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PMID:Long-term depression of a sympathetic ganglionic response to opioids by prolonged synaptic activity and by phorbol esters. 896 46


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