Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P61278 (somatostatin)
 22,083 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The present study addressed the question as to whether or not' interacting mu and delta opioid receptors, which may constitute an opioid receptor complex-inhibitory coupled to adenylate cyclase in rat neostriatum, display different antagonistic properties than the classical (noncomplexed) mu and delta receptors. In concentrations that antagonized the presynaptic inhibitory effect of [D-Ala2,MePhe4,Gly-ol5]enkephalin (DAMGO) on [3H]norepinephrine release from rat neocortical slices, the cyclic somatostatin-related mu opioid receptor antagonist D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 did not affect the inhibition of dopamine-sensitive adenylate cyclase caused by DAMGO in neostriatal slices. The delta opioid receptor antagonist naltrindole appeared to be about 200-fold more effective as an antagonist against inhibitory effect of [D-Ser2(O-tert-butyl),Leu5]enkephalyl-Thr6 on [14C]acetylcholine release from neostriatal slices than against the inhibitory effect of DAMGO on [3H]norepinephrine release from neocortical slices, in agreement with the involvement of presynaptic delta and mu receptors, respectively. However, regarding the inhibitory effect of DAMGO and [D-Ser2(O-tert-butyl),Leu5] enkephalyl-Thr6 on adenylate cyclase activity in neostriatal slices, naltrindole not only displayed a very low affinity but also only 10-fold delta-selectivity. In striking contrast to D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 and naltrindole, naloxone did not discriminate between the neurotransmitter release-and adenylate cyclase-inhibitory effects of DAMGO and [D-Ser2(O-tert-butyl), Leu5]enkephalyl-Thr6.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Opioid receptor antagonists discriminate between presynaptic mu and delta receptors and the adenylate cyclase-coupled opioid receptor complex in the brain. 132 6

The opioid receptor antagonist properties of four conformationally constrained cyclic octapeptide analogues of somatostatin were investigated using in vitro functional paradigms of mu-, delta- and kappa-opioid receptors in the rat brain. The analogues examined were D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP), D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 (CTAP), D-Tic-CTOP (TCTOP) and D-Tic-CTAP (TCTAP). Activation of mu-receptors by the enkephalin analogue Tyr-D-Ala-Gly-(NMe)Phe-Gly-ol (DAGO) inhibited the (electrically evoked) release of [3H]noradrenaline (NA) from superfused cortical slices and this inhibitory effect was antagonized in a competitive fashion by all of the octapeptides tested (pA2 values: CTOP and CTAP 7.9-8.0, TCTOP and TCTAP 8.7-8.8). Selective activation of kappa-opioid receptors by the cyclohexylbenzeneaceamide U69593 (0.02 microM) inhibited (by 40-45%) the release of [3H]dopamine (DA) from striatal slices, whereas selective activation of delta-opioid receptors by [D-Ser2(O-t-butyl),Leu5]enkephalyl-Thr6 (DSTBULET; 0.1 microM) caused an inhibition (by 38-46%) of striatal [14C]acetylcholine (ACh) release. However, these inhibitory effects were not affected by any of the octapeptides in concentrations that caused full antagonism of the inhibitory effect (55-65%) of 0.1 microM DAGO on cortical [3H]NA release. Thus, the cyclic octapeptide somatostatin analogues CTOP, CTAP, TCTOP and TCTAP are potent and highly selective antagonists at the mu-opioid receptors mediating presynaptic inhibition of NA release in the brain. The mu-receptor affinity of the most potent of these antagonists, TCTOP and TCTAP, appears to be similar to that of naloxone but these antagonists have a much greater selectivity than the latter.
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PMID:Cyclic somatostatin analogues as potent antagonists at mu-, but not delta- and kappa-opioid receptors mediating presynaptic inhibition of neurotransmitter release in the brain. 168 63

The opioid peptides are potent inhibitors of gastric somatostatin-like immunoreactivity (SLI) secretion from the isolated perfused rat stomach. In addition, inhibition of SLI secretion induced by vagal stimulation is partially blocked by naloxone, indicating that endogenously released opioid peptides probably play a physiological role in the regulation of SLI release. The opioid peptides exert their effects by interacting with a number of different receptor types. In the present study, the effect of the selective delta-opioid receptor agonists [D-Pen2.5]enkephalin and [D-Pen2,L-Pen5]enkephalin and the mu-receptor agonist [D-Ala2, N-methyl (NMe)-Phe4,Gly5-ol]enkephalin on gastric inhibitory polypeptide (GIP)-stimulated SLI secretion from the isolated perfused rat stomach have been studied. Responses to the less selective delta-agonist [D-Ala2,D-Leu5]enkephalin, dynorphins 1-8, 1-13, and 1-17, and the extended enkephalin forms Met-enkephalin-Arg6-Phe7,Met- enkephalin-Arg6-Gly7-Leu8, and Met-enkephalin-Arg6-Arg7-Val8-NH2 (metorphamide), have also been investigated. [D-Ala2,NMe-Phe4,Gly5-ol]enkephalin induced a concentration-dependent inhibition of GIP-stimulated SLI secretion, with 50% of maximal inhibition at 10 nM. Neither [D-Pen2.5]enkephalin nor [D-Pen2,L-Pen6]enkephalin (10 nM to 1 microM) had any effect on SLI release, and [D-Ala2,D-Leu5] enkephalin inhibited SLI release only at high concentrations. Met-enkephalin-Arg6-Phe7 and metorphamide both inhibited SLI release, whereas Met-enkephalin-Arg6-Gly7-Leu8 and the dynorphins had little or no effect. In conclusion, the strong inhibition of SLI secretion produced by [D-Ala2,NMe-Phe4,Gly5-ol] enkephalin and lack of major effect of [D-Pen2.5]-enkephalin, [D-Pen2,L-Pen5]enkephalin, and the dynorphins indicate that opioid peptide-induced inhibition was mediated by interaction with mu-receptors and that neither delta or kappa-receptors play a significant role.
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PMID:Characterization of the opioid receptor type mediating inhibition of rat gastric somatostatin secretion. 197 18

The effects of agonists at mu and delta opioid receptors were compared by measuring membrane currents under voltage clamp from neurons of the rat nucleus locus coeruleus and guinea pig submucous plexus. In each tissue, the appropriate selective agonist (Tyr-D-Ala-Gly-MePhe-Gly-ol for mu receptors in locus coeruleus or Tyr-D-Pen-Gly-Phe-D-Pen for delta receptors in submucous plexus) increased the conductance of an inwardly rectifying potassium conductance and strongly hyperpolarized the membrane. The properties of the potassium conductance affected by the two opioids could not be distinguished. Experiments with intracellular application of guanosine 5'-[gamma-thio]triphosphate indicated that a guanine nucleotide-binding regulatory protein was involved in the coupling between opioid receptor and potassium channel, but there was no evidence for activation of either cAMP-dependent protein kinase or protein kinase C. It is noted that a number of vertebrate neurotransmitter receptors are coupled to potassium channels. The potassium conductance associated with these channels has properties similar to the conductance activated by mu and delta opioids; this family includes the following receptors: acetylcholine M2, norepinephrine alpha 2, dopamine D2, 5-hydroxytryptamine 5-HT1, adenosine A1, gamma-aminobutyric acid GABAB, and somatostatin. It is suggested that this conductance is a conserved neuronal effector coupled to one of the receptor types that mediates the effects of each of several major transmitters. The mu and delta opioid receptors appear to be unusual in that both utilize this same effector mechanism.
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PMID:Mu and delta receptors belong to a family of receptors that are coupled to potassium channels. 244 52

1. Intracellular recordings were made from neurones in the submucous plexus of the guinea-pig caecum and ileum. 2. Somatostatin hyperpolarized more than 90% of the neurones. The lowest effective concentration was 300 pM and the maximum hyperpolarization (about 30-35 mV) was caused by 30 nM. Under voltage clamp at -60 mV, somatostatin caused outward currents which reached a maximum of 350-700 pA. 3. The hyperpolarization or outward current reversed polarity at a membrane potential (about -90 mV in control solutions) which changed according to the logarithm of the external potassium concentration. 4. The somatostatin current showed inward rectification; when the inward rectification of the resting membrane was prevented by extracellular caesium or rubidium, the inward rectification of the somatostatin current also disappeared. 5. A potassium conductance with the same properties was increased by alpha 2-adrenoceptor agonists and by delta-opioid receptor agonists; however, the effects of somatostatin were unaffected by antagonists at alpha 2- or delta-receptors. The somatostatin analogue, cyclo-aminoheptanoyl-Phe-D-Trp-Lys-(benzyl)Thr, also did not antagonize the actions of somatostatin. 6. The hyperpolarization (or outward current) was unaffected by forskolin, cholera toxin, sodium fluoride, phorbol esters or intracellular application of adenosine 5'-O-(3-thiotriphosphate) (ATP-gamma-S). However, when the recording electrode contained guanosine 5'-O-(3-thiotriphosphate) (GTP-gamma-S) the hyperpolarizations reversed only partially when somatostatin application was discontinued, and repeated applications caused the membrane potential to approach and remain close to the potassium equilibrium potential. 7. It is concluded that somatostatin increases the conductance of a set of inwardly rectifying potassium channels in submucous plexus neurones. The coupling between somatostatin receptor and ion channel involves a guanosine 5'-triphosphate-binding protein, but is not likely to result from changes in intracellular levels of cyclic adenosine 3',5'-monophosphate.
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PMID:Somatostatin increases an inwardly rectifying potassium conductance in guinea-pig submucous plexus neurones. 245 Sep 94

In the present study the opioid receptor antagonist properties of the conformationally constrained cyclic octapeptide D-Phe-Cys-Tyr-D-Trp-Lys-Thr-Pen-Thr-NH2 (CTP), which is derived from somatostatin, were investigated, using in vitro functional paradigms of central mu-, delta- and kappa-opioid receptors. Activation of mu-opioid receptors by the enkephalin analogues DADLE or DAGO resulted in a strong inhibition (by 60-70%) of the (electrically evoked) release of [3H]noradrenaline (NA) from superfused cortical slices. This inhibitory effect was antagonized by CTP in a competitive fashion (pA2 value 7.7-7.9). Activation of kappa-opioid receptors by bremazocine selectively inhibited (by 45-50%) the release of [3H]dopamine (DA) from striatal slices, whereas activation of delta-opioid receptors by DADLE caused an inhibition (by 55-60%) of striatal [14C]acetylcholine (ACh) release, but neither of these inhibitory effects was affected by CTP. By itself, CTP inhibited cortical [3H]NA release (by 35-40%), but it did not affect the release of [3H]DA nor that of [14C]ACh from striatal slices. The inhibitory effect of CTP was not antagonized by naloxone. The data indicate that CTP selectively antagonizes mu-opioid receptors, involved in presynaptic inhibition of NA release in the brain. In addition, the peptide by itself causes an inhibition of NA release via a non-opioid receptor-mediated process.
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PMID:Antagonist activity of the cyclic somatostatin analogue CTP at mu- but not delta- and kappa-opioid receptors involved in presynaptic inhibition of neurotransmitter release. 290 79

Dynorphin-[1-13], at concentrations of 5.8 X 10(-12) to 5.8 X 10(-9) M, stimulated insulin secretion from isolated islets of Langerhans of the rat, in medium containing 6 mM glucose. Higher concentrations of dynorphin had no significant effect on secretion. Dynorphin (5.8 X 10(-9) M) was unable to initiate insulin release from islets in the presence of 2 mM glucose, or to increase insulin secretion further in the presence of 20 mM glucose or 6 and 12 mM glyceraldehyde. Dynorphin-induced insulin secretion from islets was blocked by verapamil (5 microM) or by chlorpropamide (72 microM), but not by a mu opiate receptor antagonist, naloxone (0.11 microM), or by ICI 154129, a specific antagonist for the delta receptor (0.25 microM). Dynorphin had no effect on islet somatostatin secretion, under conditions in which insulin secretion was greatly stimulated. Glucose (20 mM) and glyceraldehyde (6 and 12 mM) significantly increased both insulin and somatostatin secretion. Dynorphin (5.8 X 10(-9) M) increased 45Ca2+ uptake into islets, and also increased intracellular islet c-AMP levels. These changes persisted when higher concentrations of dynorphin were used. These results suggest that (1) dynorphin is a very potent stimulus for insulin secretion; (2) dynorphin does not affect somatostatin secretion in static incubations of islets, in the same way as does glucose and glyceraldehyde; (3) dynorphin's effects may involve increased calcium ion movement and can be blocked by verapamil; (4) dynorphin can also increase islet c-AMP, and could thereby modulate the responsiveness of other secretagogues; (5) the actions of dynorphin on insulin secretion are not mediated by delta or mu opiate receptors in islets.
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PMID:Effect of dynorphin on insulin and somatostatin secretion, calcium uptake, and c-AMP levels in isolated rat islets of Langerhans. 613 34

Following the cloning of the opioid receptors mu, kappa, and delta, we conducted a search for related receptors. Using oligonucleotides based on the opioid and also the structurally related somatostatin receptors, we amplified genomic DNA using the polymerase chain reaction and isolated fragments of novel G protein-coupled receptor genes. Two of these gene fragments designated clones 12 and 11 were used to isolate the full-length genes. The intronless coding sequences of these genes, named GPR7 and GPR8, shared 70% identity with each other, and each shared significant similarity with the sequences encoding transmembrane regions of the opioid and somatostatin receptors. GPR7 was mapped to chromosome 10q11.2-q21.1 and GPR8 to chromosome 20q13.3. Northern blot analysis using human mRNA demonstrated expression of GPR7 mainly in cerebellum and frontal cortex, while GPR8 was located mainly in the frontal cortex. In situ hybridization revealed expression of GPR7 in the human pituitary. A partial sequence of the mouse orthologue of GPR7 was obtained, and in situ hybridization demonstrated expression in discrete nuclei of brain, namely suprachiasmatic, arcuate, and ventromedial nuclei of hypothalamus. A stable cell line expressing the GPR7 gene was created, but expression levels of the receptor were low. The available pharmacology indicated binding to several opioid drugs such as bremazocine, levorphanol, and beta-FNA, but not to the opioid receptor subtype-selective mu, delta, or kappa agonists.
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PMID:The cloning and chromosomal mapping of two novel human opioid-somatostatin-like receptor genes, GPR7 and GPR8, expressed in discrete areas of the brain. 759 Jul 51

The effects of cold water swim stress (CWSS) on the nociceptive responses to i.t. administered substance P (SP) and somatostatin (SST) were examined. Male ICR mice, weighing about 30 g, were forced to swim in water at 20 degrees C for 3 min. In unstressed mice, i.t. injection of SP (0.1 nmol) and SST (1 nmol), respectively, produced nociceptive-related behaviors. Although CWSS had no effect on the intensity of the SP-induced nociceptive responses, CWSS significantly reduced the intensity of the SST-induced nociceptive responses. The effect of CWSS on the SST-induced nociceptive responses was blocked by naloxone (5 mg/kg, s.c.) and naltrindole (1 mg/kg, s.c.), a selective delta-opioid receptor antagonist, but not by beta-funaltrexamine (20 mg/kg, s.c.), a selective mu-opioid receptor antagonist. These results indicate that CWSS may selectively reduce the SST-induced nociceptive responses primarily through delta-opioid receptors.
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PMID:Cold water swim stress inhibits the nociceptive responses to intrathecally administered somatostatin, but not substance P. 768 27

Members of the three classes of opioid receptors (mu, delta, and kappa) have been cloned and characterized in unexcitable cell lines using biochemical techniques. However, an important function of these cloned receptors, their coupling to voltage-activated Ca2+ channels, remains untested. We stably transfected cloned rat mu-opioid receptor cDNAs into clonal pituitary GH3 cells. GH3 cells expressing mu-opioid receptors (GH3MOR cells) bound the receptor-specific ligands [D-Ala2,Me-Phe4,Gly-ol5]-enkephalin (DAMGO) and morphine with high affinity (Ki = 1.0 and 7.2 nM, respectively), and these ligands also potently inhibited adenylyl cyclase activity (IC50 = 21.9 and 55.2 nM, respectively). Functional coupling of mu-opioid receptors to voltage-activated Ca2+ channels was compared with that of endogenous somatostatin (SRIF) receptors in GH3MOR cells, using the patch-clamp technique, with Ba2+ as the charge carrier. DAMGO (1 microM) and SRIF (1 microM) inhibited Ba2+ currents by 23.8 +/- 1.0% and 22.9 +/- 2.5%, respectively. DAMGO (0.1 nM to 10 microM) dose-dependently inhibited Ba2+ currents, with an IC50 of 105 nM. The mu-opioid receptor agonist morphine (1 microM) inhibited currents by 13.5 +/- 1.1% and the delta-opioid receptor-selective ligand [D-Pen2,5]-enkephalin (1 microM) caused only 3.5 +/- 2.1% inhibition. The inhibitory actions of DAMGO, morphine, and [D-Pen2,5]-enkephalin were reversed by naloxone. Ba2+ current inhibitions by DAMGO and SRIF were attenuated by pertussis toxin pretreatment. Nimodipine reduced the amplitude of Ba2+ current inhibition by DAMGO, suggesting that mu-opioid receptors couple to L-type Ca2+ channels in GH3MOR cells.
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PMID:Ca2+ channel and adenylyl cyclase modulation by cloned mu-opioid receptors in GH3 cells. 774 71


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