UNIPROT:P01189 - FACTA Search

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Query: UNIPROT:P01189 (beta-endorphin)
21,003 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In mice whose Gi/o-protein function had been impaired by antisense 'knock-down' or pertussis toxin treatment, i.c.v. injection of myr+-Gi/o alpha subunits restored the effectiveness of beta-endorphin, morphine, DPDPE, clonidine and neurotensin to produce antinociception. Myr+-G alpha subunits of the class of G-proteins actually impaired were more effective than unlike but related myr+-G alpha subunits. Selectivity was noted in that only exogenous myr+-G alpha subunits affected (enhanced) the activity of agonists in G alpha-deficient signalling systems. This treatment had little effect on agonist potency when the impairment resided at the receptor level. The potential of the opioids, clonidine and R-PIA to increase G alpha-related in vitro hydrolysis of GTP was also re-established after injecting myr+-Gi2 alpha subunits into Gi2-knocked-down mice. Myr+-Gi2 alpha subunits pre-incubated with GTPgammaS or GDPbetaS before i.c.v. injection did not improve the activity of agonists in vivo (antinociception) or in vitro (regulation of low Km GTPase). After impairing the function of PKCbeta1 by antisense treatment or with the inhibitor H7, the effect of myr+-G alpha subunits on agonist potency was prevented. Electron microscope analysis showed the entry of gold-conjugated myr+-G alpha subunits into neural cells. These particles were found in the cytoplasm, associated with the plasma membranes of different neuronal processes and also in synaptic junctions. In cultured neurons and astrocytes myr+-Gi2 alpha-associated fluorescence was internalised in a dose-dependent manner and distributed in the plasma membrane and cytosol, as well as in nuclei of dividing astrocytes. Thus, G alpha subunits in CSF enter into neurons and functionally couple to the receptor-triggered signalling cascade. As G-proteins have been implicated in the pathophysiology of several neural disorders, this finding may be valuable in the therapy of such dysfunctions.
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PMID:Myr+-Gi2 alpha and Go alpha subunits restore the efficacy of opioids, clonidine and neurotensin giving rise to antinociception in G-protein knock-down mice. 1060 81

The binding of [(125)I] orexin-A (Ox-A) to particulates from Chinese hamster ovary (CHO) cells expressing the cloned orexin-A receptor, or from rat forebrain areas, was sensitive to blockers of phosphatidylinositol-specific phospholipase C (PtdIns-PLC) U-73122 and ET-18-OCH(3), little affected by phospholipase A(2) inhibitor quinacrine, and not sensitive to D609, a xanthate inhibitor of phosphatidylcholine-selective PLC. Interaction of the receptor with a PtdIns-PLC was further indicated by a large sensitivity of the binding to Ca(2+). Up to 50% of the binding was sensitive to the G-protein nucleotide site agonist GTP-gamma-S. Ligand attachment to the orexin-A receptor thus depends on an association with both PtdIns-PLC and G-protein alpha-subunits. In all paradigms examined, the binding of [(125)I]orexin-A was competed by human/rat neuropeptide Y (hNPY) and porcine secretin with a potency similar to orexin-A (IC(50) range 30-100 nM). The rank order of potency for NPY-related peptides was hNPY > porcine peptide YY (pPYY) > (Leu(31), Pro(34)) human PYY > human PYY(3-36) > hNPY free acid > human pancreatic polypeptide. Among secretin-related peptides, the rank order of potency was porcine secretin > or = orexin-A > human pituitary adenylate cyclase-activating peptide > orexin-B > porcine vasoactive intestinal peptide. Among opioid peptides, rat beta-endorphin and camel delta-endorphin were much less active than NPY and secretin, and two enkephalins were inactive at 1 microM. In view of high abundance of NPY in forebrain, the above cross-reactivity could indicate a significant contribution of NPY to signaling via orexin-A receptors.
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PMID:Sensitivity of orexin-A binding to phospholipase C inhibitors, neuropeptide Y, and secretin. 1086 Aug 58

The activation of mu-, delta- and kappa1-opioid receptors by their respective agonists increases the binding of the non-hydrolyzable GTP analog guanosine-5'-(gamma-thio)-triphosphate (GTPgammaS) to G proteins. Beta-endorphin is an endogenous opioid peptide which binds nonselectively to mu-, delta- and putative epsilon-opioid receptors. The present experiment was designed to determine which opioid receptors are involved in the stimulation of [35S]GTPgammaS binding induced by beta-endorphin in the mouse pons/medulla. The mouse pons/medulla membranes were incubated in an assay buffer containing 50 pM [35S]GTPgammaS, 30 microM GDP and various concentrations of beta-endorphin. Beta-endorphin (0.1 nM-10 microM) increased [35S]GTPgammaS binding in a concentration-dependent manner, and 10 microM beta-endorphin produced a maximal stimulation of approximately 260% over baseline. This stimulation of [35S]GTPgammaS binding by beta-endorphin was partially attenuated by the mu-opioid receptor antagonist beta-funaltrexamine (beta-FNA), but not by the delta-opioid receptor antagonist naltrindole (NTI) or the kappa1-opioid receptor antagonist nor-binaltorphimine (nor-BNI). Beta-endorphin stimulated [35S]GTPgammaS binding by about 80% in the presence of 10 microM beta-FNA, 30 nM NTI and 100 nM nor-BNI. The same concentrations of these antagonists completely blocked the stimulation of [35S]GTPgammaS binding induced by 10 microM [D-Ala2,NHPhe4,Gly-ol]enkephalin, [D-Pen(2,5)]enkephalin and U50,488H, respectively. Moreover, the residual stimulation of [35S]GTPgammaS binding induced by beta-endorphin in the presence of the three opioid receptor antagonists was significantly attenuated by 100 nM of the putative epsilon-opioid receptor partial agonist beta-endorphin (1-27). These results indicate that the stimulation of [35S]GTPgammaS binding induced by beta-endorphin is mediated by the stimulation of both mu- and putative epsilon-opioid receptors in the mouse pons/medulla.
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PMID:Activation of G-proteins in the mouse pons/medulla by beta-endorphin is mediated by the stimulation of mu- and putative epsilon-receptors. 1110 89

This paper reports that regulators of G-protein signalling (RGS) proteins modulate the timing and amplitude of opioid signals by a push-pull mechanism. This is achieved without noticeable changes in the binding properties of opioids, e.g. beta-endorphin to mu-opioid receptors. The expression of RGS proteins was reduced by blocking their mRNA with antisense oligodeoxynucleotides (ODN). Knock down of RGS2 or RGS3 diminished morphine and beta-endorphin analgesia, whereas that of RGS9 or RGS12 enhanced this activity. In mice with impaired RGS9, but not impaired RGS2, the potency and, in particular, the duration of opioid antinociception increased. Further, the animals did not exhibit acute tolerance generated by a single and efficacious dose of morphine, nor did they develop tolerance after a daily i.c.v. injection of the opioid for 4 days. In a model of sustained morphine treatment, the impairment of RGS9 proteins facilitated increases in the response to the delivered opioid. This was only effective for 2--3 h after the subcutaneous implantation of an oily morphine pellet; later, tolerance developed. To reduce the impact of the chronic morphine acting on opioid receptors, other RGS proteins presumably substitute the GTPase-activating function of RGS9 on morphine-activated G-alpha-GTP subunits. The desensitization of mu-opioid receptors appears to be a cell membrane-limited process facilitated by RGS9's sequestering of agonist-segregated G alpha subunits.
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PMID:RGS9 proteins facilitate acute tolerance to mu-opioid effects. 1120 15

The luminal domains of membrane peptidylglycine alpha-amidating monooxygenase (PAM) are essential for peptide alpha-amidation, and the cytosolic domain (CD) is essential for trafficking. Overexpression of membrane PAM in corticotrope tumor cells reorganizes the actin cytoskeleton, shifts endogenous adrenocorticotropic hormone (ACTH) from mature granules localized at the tips of processes to the TGN region, and blocks regulated secretion. PAM-CD interactor proteins include a protein kinase that phosphorylates PAM (P-CIP2) and Kalirin, a Rho family GDP/GTP exchange factor. We engineered a PAM protein unable to interact with either P-CIP2 or Kalirin (PAM-1/K919R), along with PAM proteins able to interact with Kalirin but not with P-CIP2. AtT-20 cells expressing PAM-1/K919R produce fully active membrane enzyme but still exhibit regulated secretion, with ACTH-containing granules localized to process tips. Immunoelectron microscopy demonstrates accumulation of PAM and ACTH in tubular structures at the trans side of the Golgi in AtT-20 cells expressing PAM-1 but not in AtT-20 cells expressing PAM-1/K919R. The ability of PAM to interact with P-CIP2 is critical to its ability to block exit from the Golgi and affect regulated secretion. Consistent with this, mutation of its P-CIP2 phosphorylation site alters the ability of PAM to affect regulated secretion.
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PMID:Signaling mediated by the cytosolic domain of peptidylglycine alpha-amidating monooxygenase. 1125 Oct 76

1. We used the patch-clamp technique, in conjunction with membrane capacitance measurement, fluorescence measurement of intracellular calcium concentration ([Ca(2+)](i)), and flash photolysis of caged Ca(2+) to study exo- and endocytosis in identified rat corticotrophs. 2. Exocytosis stimulated by depolarization pulses was typically followed by a 'slow' endocytosis that retrieved the membrane with a time constant of approximately 6 s. The efficiency (the endocytosis/exocytosis amplitude ratio) of 'slow' endocytosis was approximately 1.2 at [Ca(2+)](i) < 3 microM and increased to approximately 1.6 at [Ca(2+)](i) > 3 microM. 3. Whole-cell dialysis through a patch pipette did not affect the kinetics and the efficiency of 'slow' endocytosis, but the amplitude of exocytosis was reduced. 4. 'Slow' endocytosis did not require sustained [Ca(2+)](i) elevation and its kinetics was only weakly [Ca(2+)](i) dependent. Our results suggest that 'slow' endocytosis involves a Ca(2+) sensor with a high Ca(2+) affinity (approximately 500 nM). 5. At high [Ca(2+)](i) (> 10 microM), the 'slow' endocytosis was frequently preceded by a 'fast' endocytosis that comprised multiple steps of rapid decrease in membrane capacitance. 6. Neither calmodulin nor calcineurin appeared to be the Ca(2+) sensor for endocytosis because the two forms of endocytosis were not affected by the calmodulin inhibitor calmidazolium (500 microM) or the calcineurin inhibitors cyclosporin A (1 microM) and calcineurin autoinhibitory peptide (1 mg ml(-1)). Ba(2+), a poor activator of calmodulin, could support both forms of endocytosis but slowed the kinetics of 'slow' endocytosis approximately 2-fold. 7. Non-hydrolysable analogues of GTP (GDP-beta-S) and ATP (ATP-gamma-S) also failed to inhibit either form of endocytosis, indicating that neither GTP nor ATP was essential for endocytosis. 8. We suggest that the high Ca(2+) affinity of 'slow' endocytosis may be important for maintaining continuous cycles of exocytosis-endocytosis during sustained adrenocorticotropin secretion in corticotrophs.
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PMID:Endocytosis in identified rat corticotrophs. 1138

A number of studies have shown that activation of gamma-aminobutyric acid(B) (GABA(B)) receptors potentiates neurotransmitter-induced accumulation of cyclic AMP in brain slices, but the mechanisms involved in the facilitatory effect have not been fully elucidated. In the present study, we showed that in membranes of rat frontal cortex the GABA(B) receptor agonist (-)baclofen increased basal adenylyl cyclase activity and potentiated the maximal enzyme stimulation elicited by corticotropin-releasing hormone (CRH). The less active enantiomer (+)baclofen had no effect on cyclic AMP formation, whereas the natural agonist GABA mimicked the stimulatory action of (-)baclofen. In radioligand-binding experiments, the affinity and maximal binding capacity of (125)I-Tyr-CRH was not affected by (-)baclofen. The GABA(B) receptor antagonist CGP 55845A competitively counteracted the (-)baclofen potentiation of CRH-stimulated adenylyl cyclase activity with a pA(2) value of 6.70. Moreover, both (-)baclofen and GABA, but not (+)baclofen, caused a concentration-dependent stimulation of [(35)S]GTP gamma S binding to membrane G-proteins. The intracerebral injection of pertussis toxin significantly reduced the facilitatory effects of (-)baclofen on both basal and CRH-stimulated adenylyl cyclase activities. Moreover, membrane incubation with the GDP-bound form of the alpha subunit of transducin, a scavenger of G protein beta gamma subunits, blocked the stimulatory effects of (-)baclofen. The data indicate that in rat frontal cortex activation of GABA(B) receptors potentiates the CRH stimulation of adenylyl cyclase activity through a mechanism involving the beta gamma subunits of the pertussis toxin-sensitive G protein G(i)/G(o).
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PMID:Beta gamma-mediated enhancement of corticotropin-releasing hormone-stimulated adenylyl cyclase activity by activation of gamma-aminobutyric acid(B) receptors in membranes of rat frontal cortex. 1138 76

Bovine adrenal zona fasciculata (AZF) cells express two types of K(+)-selective ion channels including a rapidly inactivating bKv1.4 current (I(A)) and an ATP-dependent noninactivating background current (I(AC)) that sets the resting membrane potential. Whole-cell, patch-clamp recording from cultured AZF cells was used to demonstrate a novel reciprocal modulation of these two K(+) channels by intracellular nucleotides and corticotropin. Specifically, increases in I(AC) activity induced by intracellular ATP, as well as GTP and 5'-adenylyl-imidodiphosphate (AMP-PNP), were accompanied by a corresponding decrease in the amplitude of the voltage-gated I(A) current. The reduction in I(A) current was observed only when patch pipettes contained ATP or other nucleotides at concentrations sufficient to support activation of I(AC). Conversely, the nearly complete inhibition of I(AC) by corticotropin was accompanied by the coincident reappearance of functional I(A) channels. In the absence of I(AC) current, corticotropin failed to alter I(A). The reciprocal modulation of AZF cell K(+) channels by nucleotides and corticotropin was independent of membrane voltage. These results demonstrate a new form of channel modulation in which the activity of two different K(+) channels is reciprocally modulated in tandem through hormonal and metabolic signaling pathways. They further suggest that I(A) and I(AC) K(+) channels may be functionally coupled in a dynamic equilibrium driven by intracellular ATP and G-protein-coupled receptors. This may represent a unique mechanism for transducing biochemical signals to ionic events involved in cortisol secretion.
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PMID:Reciprocal modulation of voltage-gated and background K(+) channels mediated by nucleotides and corticotropin. 1140 6

An ATP diphosphohydrolase was identified in the plasma membranes isolated from promastigote forms of Leishmania amazonensis. Both ATP and ADP were hydrolysed at similar rates by the enzyme. Other nucleotides such as UTP, GTP and CTP were also degraded, revealing a broad substrate specificity. Adding ATP and ADP simultaneously, the amount of hydrolysis achieved was compatible with the presence of a single enzyme. ATPase activity was not affected by addition of vanadate, ouabain, thapsigargin, dicyclohexylcarbodiimide, oligomycin and bafilomycin A, thus excluding involvement of P-, F- and V-type ATPases. The effects of pH in the range 6.5-8.5 were examined using ATP or p-NPP as substrate. At pH 7.4, the phosphatase activity decreased, and did not show a significant contribution to ATP hydrolysis. In addition, the enzyme was not inhibited by levamisole and ammonium molybdate, excluding alkaline phosphatase and nucleotidase activities, respectively. Sodium azide (5-10 mM) caused inhibition of the ATP and ADP hydrolysis in a dose-dependent manner. Calcium was the best activating metal ion for both ATPase and ADPase activities. Ultrastructural cytochemical microscopy showed ATP diphosphohydrolase on the surface and flagellar pocket of the parasite. We have proposed that L. amazonensis ATP diphosphohydrolase may participate in the salvage pathway of nucleosides.
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PMID:Characterization and cytochemical localization of an ATP diphosphohydrolase from Leishmania amazonensis promastigotes. 1186 92

Here we report antimitogenic mechanisms activated by the adrenocorticotropic hormone (ACTH) in the mouse Y1 adrenocortical tumor cell line. ACTH receptors activate the Galphas/adenylate cyclase cAMP/PKA pathway to promote dephosphorylation of Akt/PKB enzymes, leading to induction of the cyclin-dependent kinases' (CDKs) inhibitor p27(Kip1). Y1 cells display high constitutive levels of phosphorylated Akt/PKB dependent on chronically elevated c-Ki-Ras.GTP and PI3K activity. Expression of the dominant negative mutant RasN17 in Y1 cells results in strong reduction of both c-Ki-Ras.GTP and phosphorylated Akt/PKB, which are restored by FGF2 treatments. Inhibitors of PI3K lead to rapid dephosphorylation of Akt/PKB and block phosphorylation of Akt/PKB promoted by FGF2. ACTH rapidly promotes dephosphorylation of Akt/PKB in Y1 adrenal cells, while constitutively high levels of c-Ki-Ras.GTP remain unchanged. ACTH and cAMP elevating agents fail to cause Akt/PKB dephosphorylation in PKA-deficient clonal mutants of Y1 cells. In addition, cholera toxin, forskolin, and 8BrcAMP all mimic ACTH, causing dephosphorylation of Akt/PKB in wild-type Y1 cells. ACTH is unable to prevent Akt/PKB phosphorylation, promoted by FGF2 in clonal lines of RasN17-Y1 transfectants displaying negligible levels of c-Ki-Ras.GTP. ACTH promotes strong p27(Kip1) protein induction in wild-type Y1 adrenocortical cells but not in PKA-deficient Y1-clonal mutants nor in RasN17-Y1 transfectants. PI3K inhibitors induce p27(Kip1) protein in all cells studied, i.e., wild type and transfectants. The inverse correlation between levels of phosphorylated Akt/PKB and of p27(Kip1) protein caused by ACTH suggests a novel antimitogenic pathway activated by ACTH and mediated by cAMP/PKA in the mouse Y1 adrenocortical tumor cell line.
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PMID:ACTH promotion of p27(Kip1) induction in mouse Y1 adrenocortical tumor cells is dependent on both PKA activation and Akt/PKB inactivation. 1214 78

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