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)

Previous reports have demonstrated that corticotropin-releasing hormone (CRH) treatment of primary cultures of mouse Leydig cells and MA-10 mouse Leydig tumor cells results in a dose-dependent stimulation of steroidogenesis, probably by acting through the cAMP/protein kinase A second messenger pathway. Based on this observation, the mechanism of CRH-stimulated steroidogenesis is now further investigated and compared to trophic hormone stimulation. Both cell types were treated with human chorionic gonadotropin (hCG) or CRH in the absence and presence of the following agents: the translation inhibitor cycloheximide, the transcription inhibitor actinomycin D, the protonophore carbonyl cyanide m-chlorophenylhydrozone (mCCCP), which disrupts the mitochondrial electrochemical gradient or the phorbol ester, phorbol-12-myristate 13-acetate (PMA), a stimulator of protein kinase C. Cortico-releasing hormone-stimulated steroidogenesis was completely blocked by cycloheximide in both cell types, indicating that CRH-stimulated steroidogenesis in mouse Leydig cells requires ongoing protein synthesis. Actinomycin D had profound inhibitory effects on CRH-stimulated steroidogenesis in MA-10 cells, and this inhibition was greater than that seen in mouse primary Leydig cells. mCCCP severely inhibited CRH-stimulated steroid production in both cell types, indicating that an electrochemical gradient across the inner mitochondrial membrane is required for CRH-stimulated steroidogenesis. In addition, PMA inhibited hCG- and CRH-stimulated steroidogenesis in MA-10 cells and CRH-stimulated steroidogenesis in primary Leydig cells, suggesting that activation of the protein kinase C pathway can influence protein kinase A stimulated steroidogenesis. Results of these studies suggest that the mouse Leydig cell steroidogenic response to CRH shares many similarities to that of the LH response.
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PMID:The cellular mechanisms of corticotropin-releasing hormone (CRH)-stimulated steroidogenesis in mouse Leydig cells are similar to those for LH. 934 51

Mu opioid receptors are subject to phosphorylation and desensitization through actions of at least two distinct biochemical pathways: agonist-dependent mu receptor phosphorylation and desensitization induced by a biochemically distinct second pathway dependent on protein kinase C activation (1). To better understand the nature of the agonist-induced mu receptor phosphorylation events, we have investigated the effects of a variety of opiate ligands of varying potencies and intrinsic activities on mu receptor phosphorylation and desensitization. Exposure to the potent full agonists sufentanil, dihydroetorphine, etorphine, etonitazine, and [D-Ala2, MePhe4, Glyol5]enkephalin (DAMGO) led to strong receptor phosphorylation, while methadone, l-alpha-acetylmethadone (LAAM), morphine, meperidine, DADL, beta-endorphin(1-31), enkephalins, and dynorphin A(1-17) produced intermediate effects. The partial agonist buprenorphine minimally enhanced receptor phosphorylation while antagonists failed to alter phosphorylation. Buprenorphine and full antagonists each antagonized the enhanced mu receptor phosphorylation induced by morphine or DAMGO. The rank order of opiate ligand efficacies in producing mu receptor-mediated functional desensitization generally paralleled their rank order of efficacies in producing receptor phosphorylation. Interestingly, the desensitization and phosphorylation mediated by methadone and LAAM were disproportionate to their efficacies in two distinct test systems. This generally good fit between the efficacies of opiates in mu receptor activation, phosphorylation, and desensitization supports the idea that activated receptor/agonist/G-protein complexes and/or receptor conformational changes induced by agonists are required for agonist-induced mu receptor phosphorylation. Data for methadone and LAAM suggest possible contribution from their enhanced desensitizing abilities to their therapeutic efficacies.
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PMID:Mu opioid receptor phosphorylation, desensitization, and ligand efficacy. 936 Sep 54

We have investigated the signal transduction pathway of the G-protein mu-opioid receptor upstream of phospholipase D (PLD) and protein kinase C-epsilon (PKC-epsilon) activation in postmitotic E6CH chick embryo cortical neurons. The mu-opioid receptor and PLD-PKC-epsilon functional coupling depends on upstream tyrosine kinase activation. We now report that the mu-opioid agonists specifically stimulated tyrosine phosphorylation and activation of the focal adhesion kinase (FAK) in a time-dependent manner. We also demonstrate that met-enkephalin, a mu-opioid agonist in E6CH cultures, significantly increases tyrosine phosphorylation of another Src kinase substrate, the cytoskeletal protein cortactin. Tyrosine phosphorylation of cortactin led to drastic changes in subcellular localization, an estimated 2-fold enrichment in the cytosol. Similarly, opioids stimulated a sustained tyrosine phosphorylation of vinculin, a protein enriched in focal adhesion sites. These data provide novel evidence that opioid receptor intracellular signaling engages the specific activation of tyrosine kinase FAK and regulates the neuronal cytoskeleton during central nervous system morphogenesis.
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PMID:mu-Opioids activate tyrosine kinase focal adhesion kinase and regulate cortical cytoskeleton proteins cortactin and vinculin in chick embryonic neurons. 936 24

Adrenomedullin (ADM) is a polypeptide originally discovered in a human pheochromocytoma and is also present in normal adrenal medulla. It has been proposed that ADM could be involved in the regulation of adrenal steroidogenesis via paracrine mechanisms. Our aim was to find out if ADM gene is expressed in adrenocortical tumors and how ADM gene expression is regulated in adrenal cells. ADM mRNA was detectable by Northern blotting in most normal and hyperplastic adrenals, adenomas and carcinomas. The average concentration of ADM mRNA in the hormonally active adrenocortical adenomas was about 80% and 7% of that in normal adrenal glands and separated adrenal medulla respectively. In adrenocortical carcinomas, the ADM mRNA concentration was very variable, but on average it was about six times greater than that in normal adrenal glands. In pheochromocytomas, ADM mRNA expression was about ten times greater than that in normal adrenals and three times greater than in separated adrenal medulla. In primary cultures of normal adrenal cells, a protein kinase C inhibitor, staurosporine, reduced ADM mRNA accumulation in a dose- and time-dependent fashion (P < 0.01), whereas it simultaneously increased the expression of human cholesterol side-chain cleavage enzyme (P450 scc) gene (a key gene in steroidogenesis). In cultured Cushing's adenoma cells, adrenocorticotropin, dibutyryl cAMP ((Bu)2cAMP) and staurosporine inhibited the accumulation of ADM mRNA by 40, 50 and 70% respectively (P < 0.05), whereas the protein kinase C activator, 12-O-tetradecanoyl phorbol 13-acetate (TPA), increased it by 50% (P < 0.05). In primary cultures of pheochromocytoma cells, treatment with (Bu)2cAMP for 1 and 3 days increased ADM mRNA accumulation two- to threefold (P < 0.05). Our results show that ADM mRNA is present not only in adrenal medulla and pheochromocytomas, but also in adrenocortical neoplasms. Both protein kinase A- and C-dependent mechanisms regulate ADM mRNA expression in adrenocortical and pheochromocytoma cells supporting the suggested role for ADM as an autocrine or paracrine (or both) regulator of adrenal function.
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PMID:Adrenomedullin gene expression and its different regulation in human adrenocortical and medullary tumors. 948 93

We have shown previously that noradrenaline (NA) stimulated or inhibited the release of corticotropin-releasing hormone (CRH) according to the availability of adrenal steroids. The aim of the present work was to examine whether the changes in the NA modulation of CRH release from hypothalamic neurons result from a steroid-induced plasticity of the adrenergic transduction pathways. From anterior hypothalamic slices cultured in standard medium (i.e., containing adrenal steroids at a final dilution of 61 +/- 9 ng/ml), (a) the stimulatory effect of NA on CRH release was reversed in a dose-dependent manner by increasing concentrations of the alpha1-adrenoreceptor antagonist prazosin, (b) activation of protein kinase C by acute treatment with phorbol 12-myristate 13-acetate (0.5 microM, 1 h) mimicked NA stimulation of CRH secretion, and (c) the activation of L-type Ca2+ channels by Bay K 8644 also produce an increased CRH secretion. In contrast, the inhibitory effect of NA on CRH secretion from slices cultured in steroid-free medium was markedly reversed by the alpha2-adrenoreceptor antagonist yohimbine, by pretreatment with pertussin toxin, or by the addition of 4-aminopyridine, a K+-channel blocker. Acute treatment with phorbol 12-myristate 13-acetate did not change the inhibitory NA effect. Moreover, all these effects were reversed by daily corticosterone supplementation, for as long as they were tested. These results are consistent with a steroid-dependent change in the nature of adrenergic receptors and its associated transduction pathways involved in the regulation of CRH secretion in the hypothalamus.
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PMID:Glucocorticoids provoke a shift from alpha2- to alpha1-adrenoreceptor activities in cultured hypothalamic slices leading to opposite noradrenaline effect on corticotropin-releasing hormone release. 948 42

Both urocortin (UCN) and corticotropin-releasing hormone (CRH) are known to stimulate secretion of adrenocorticotropic hormone (ACTH) by corticotroph cells via type-1 corticotropin-releasing hormone receptor (CRHR-1). We extensively examined UCN effects on the anterior pituitary (AP), particularly on proopiomelanocortin (POMC) mRNA and CRHR-1 mRNA as well as ACTH secretion in vivo. Moreover, signal transduction with UCN exposure was assessed in AP cell cultures in comparison with transduction following CRH exposure. Intravenously administered of UCN (5 microg/kg) increased ACTH and corticosterone secretion. Similarly, intravenous administration of UCN increased POMC mRNA and decreased CRHR-1 mRNA in the AP. These UCN effects were more potent and long-lasting than those of CRH. The prominent effect of UCN on ACTH secretion in vivo was confirmed in AP cell cultures, where application of UCN stimulated ACTH release approximately 7 times more strongly than CRH. The effect of UCN on ACTH release was enhanced by phorbol esters which activate protein kinase C, but was reduced by the selective cAMP-dependent protein kinase inhibitor, H-89. These results suggest that, as with CRH, UCN stimulates ACTH production and/or release through cAMP-dependent mechanisms, and that protein kinase C-dependent mechanism has a synergistic effect upon UCN-induced ACTH release. The more potent effects of UCN relative to CRH may be attributable to UCN's higher affinity for CRHR-1.
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PMID:Effect of urocortin on ACTH secretion from rat anterior pituitary in vitro and in vivo: comparison with corticotropin-releasing hormone. 973 15

Corticotropin is produced by keratinocytes and may have an immunoregulatory role in oral mucosa and skin. We have investigated its effects on a human oral keratinocyte cell line and shown that corticotropin, acting via its specific receptor, stimulates a dose-dependent increase in DNA synthesis and induces cell proliferation. When cells were incubated in the presence of increasing concentrations of corticotropin, there were significant increases in intracellular cAMP levels. Corticotropin-stimulated mitogenesis and cell proliferation were attenuated by the adenylyl cyclase inhibitor SQ22,536, but were unaffected by inhibitors of protein kinase C or tyrosine kinase. These data identify corticotropin as a mitogenic regulatory peptide of keratinocytes acting via cAMP.
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PMID:Direct effects of corticotrophin on oral keratinocyte cell proliferation. 974 48

Pituitary adenylate cyclase activating polypeptide-27 (PACAP-27) caused a dose-dependent increase in met-enkephalin secretion and increased production of met-enkephalin peptide and proenkephalin A (PEnk) mRNA in bovine chromaffin cells, at concentrations as low as 300 pM. PACAP-38 was less potent than PACAP-27, but had similar effects. Vasoactive intestinal polypeptide (VIP) (1-100 nM) was without appreciable effect on either enkephalin secretion or biosynthesis, implicating PACAP type I receptors in PACAP-stimulated enkephalin secretion and synthesis. PACAP type I receptors can activate adenylate cyclase and stimulate phospholipase C through heterotrimeric G protein interactions, leading to increased intracellular cyclic AMP (cAMP), inositol triphosphate (IP3)-mediated calcium mobilization, and calcium- and diacylglycerol (DAG)-mediated protein kinase C (PKC) activation. Enkephalin secretion evoked by 10-100 nM PACAP-27 was not inhibited by 1 microM (-)-202-791, an L-type specific dihydropyridine calcium channel blocker, but was inhibited 65-80% by the arylalkylamine calcium channel blocker D600. Forty mM potassium-evoked secretion was inhibited > 90% by both D600 and (-)-202-791, 25 microM forskolin-induced secretion was blocked < 50% by D600 and was unaffected by (-)-202-791, and 100 nM phorbol myristate acetate (PMA)-induced secretion was unaffected by either D600 or (-)-202-791. Enkephalin biosynthesis was increased by 10 nM PACAP-27, as measured by increased met-enkephalin pentapeptide content and PEnk A mRNA levels. PACAP-, forskolin-, and PMA-stimulated enkephalin synthesis were not blocked by D600 or (-)-202-791. Elevated potassium-induced enkephalin biosynthesis upregulation was completely blocked by either D600 or (-)-202-791 at the same concentrations. PACAP acting through type I PACAP receptors couples calcium influx-dependent enkephalin secretion and calcium influx-independent enkephalin biosynthesis in chromaffin cells. Restriction of the effects of enhanced calcium influx to stimulation of secretion, but not of biosynthesis, is unique to PACAP. By contrast, potassium-induced enkephalin biosynthesis upregulation is completely calcium influx dependent, specifically via calcium influx through L-type calcium channels. We propose that subpopulations of voltage-dependent calcium channels are differentially linked to intracellular signal transduction pathways that control neuropeptide gene expression and secretion in chromaffin cells.
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PMID:PACAP activates calcium influx-dependent and -independent pathways to couple met-enkephalin secretion and biosynthesis in chromaffin cells. 982 85

The intracellular regulation of adrenocorticotropin (ACTH) secretion from pituitary corticotroph cells was investigated by simultaneously exposing cultured ovine corticotrophs to arginine vasopressin (AVP) and raised extracellular K+ concentration ([K+]e). Both of these secretagogues activate L-type voltage-sensitive calcium channels (L-VSCC) as part of their respective ACTH secretory responses. When given together at high concentrations, AVP and raised [K+]e caused ACTH responses that were smaller in magnitude than the sum of the individual responses. However, at low agonist concentrations the simultaneous responses were greater in magnitude (i.e., synergistic). Further investigation suggested that activation of protein kinase C (PKC), which is part of the AVP-induced intracellular signalling pathway, is necessary and sufficient for the generation of the synergistic response, although it is not obligatory for AVP-induced ACTH release.
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PMID:Interaction between arginine vasopressin- and raised extracellular potassium-stimulated pathways in adrenocorticotropin secretion. 987 Jul 9

Under control incubation conditions, gonadotropin-releasing hormone (GnRH) binds only a fraction of its receptors in rat-cultivated pituitary cells. Unmasking of the remaining receptors, which have been termed 'cryptic', requires drug- or peptide-induced protein kinase activation. Spontaneous masking however is not observed on pituitary cells sampled from castrated male rats, suggesting the presence of an intrinsic unmasking factor. Many endogenous factors could theoretically account for the effect. Here we attempted to identify the factor involved by taking advantage of their differential dependency upon second messengers and transduction cascades. Spontaneous unmasking of GnRH binding was found reversed by pertussis toxin (PTX), an inhibitor of alphai and alphao subunits of heterotrimeric G proteins, and by U73122, a phospholipase C (PLC) inhibitor. In contrast, desensitization of protein kinase C (PKC) or inhibition of tyrosine kinase by herbimycin were ineffective. Among endogenous pituitary factors able to unmask GnRH receptors in pituitary cells from normal male rats, as EGF, NPY or opiate peptides, only the latter were found to correspond to this transduction profile. In an attempt to characterize the pharmacology of opiate effects, naloxone (10 microM), a poorly selective opiate antagonist, restored masking of GnRH binding in cells from castrates. Only the delta antagonist naltrindole (1 microM) was able to mimick the action of naloxone. Conversely, when tested on cells from intact animals, morphine (10 microM), as well as dslet (1 microM) and met-ENK (10 nM), preferential delta agonists, but not dago and beta-endorphin or U50488 H and dynorphin, respectively micro and kappa agonists, were able to suppress masking. Among opioid peptides endogenous to the pituitary, only met-ENK was able to unmask cryptic receptors, an effect antagonized by naltrindole. We conclude that an opiate delta receptor subtype is endogenously activated in the pituitary of castrated male rats to prevent masking of GnRH binding.
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PMID:Delta opiate receptors account for the castration-induced unmasking of gonadotropin-releasing hormone binding sites in the rat pituitary. 987 2


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