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

Re-188-RC-160, a radiolabeled somatostatin analogue, is being explored for its potential as a local/regionally administered radiotherapeutic agent targeting somatostatin receptor-positive tumors. In studies in vitro and in vivo, Re-188-RC-160 was found to bind to somatostatin receptor-positive cells (NCI-H69, human small cell lung carcinoma), but not to binding-negative cells (Raji, Burkitt's lymphoma). The comparative binding of Re-188-labeled RC-160 [cyclic NH2-(D)-Phe-Cys-Try-(D)-Trp-Lys-Val-Cys-Trp-NH2] or CTOP [cyclic NH2-(D)-Phe-Cys-Try-(D)-Trp-Orn-Thr-Pen-Thr-ol], a mu-opioid receptor antagonist used a negative control compound, was also determined in vitro and in vivo using NCI-H69 cells as targets. Re-188-RC-160 demonstrated higher net binding in vitro and in vivo compared to Re-188-RC-CTOP, and in vitro its binding could be reduced by excess unlabeled RC-160 whereas binding of Re-188-CTOP could not be reduced. Using another somatostatin receptor-positive human tumor line, ZR-75-1, a substantial amount of the cell-bound Re-188-RC-160 was found to be internalized. Does estimates for Re-188-RC-160 in animals containing NCI-H69 tumors indicated that with three serial injections therapeutic doses greater than 60 Gy can be achieved.
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PMID:Targeting peptides for pleural cavity tumor radiotherapy: specificity and dosimetry of Re-188-RC-160. 908 34

Growth hormone-releasing peptides (GHRPs) are synthetic, non-natural peptides endowed with potent stimulatory effects on somatotrope secretion in animals and humans. They have no structural homology with GHRH and act via specific receptors present either at the pituitary or the hypothalamic level both in animals and in humans. The GHRP receptor has recently been cloned and, interestingly, it does not show sequence homology with other G-protein-coupled receptors known so far. This evidence strongly suggests the existence of a natural GHRP-like ligand which, however, has not yet been found. The mechanisms underlying the GHRP effect are still unclear. At present, several data favor the hypothesis that GHRPs could act by counteracting somatostatinergic activity both at the pituitary and the hypothalamic level and/or, at least partially, via a GHRH-mediated mechanism. However, the possibility that GHRPs act via an unknown hypothalamic factor (U factor) is still open. GHRP-6 was the first hexapeptide to be extensively studied in humans. More recently, a heptapeptide, GHRP-1, and two other hexapeptides, GHRP-2 and Hexarelin, have been synthesized and are now available for human studies. Moreover, non-peptidyl GHRP mimetics have been developed which act via GHRP receptors and their effects have been clearly demonstrated in animals and in humans in vivo. Among non-peptidyl GHRPs, MK-0677 seems the most interesting molecule. The GH-releasing activity of GHRPs is marked and dose-related after intravenous, subcutaneous, intranasal and even oral administration. The effect of GHRPs is reproducible and undergoes partial desensitization, more during continuous infusion, less during intermittent administration: in fact, prolonged administration of GHRPs increases IGF-1 levels both in animals and in humans. The GH-releasing effect of GHRPs does not depend on sex but undergoes age-related variations. It increases from birth to puberty, persists at a similar level in adulthood and decreases thereafter. By the sixth decade of life, the activity of GHRPs is reduced but it is still marked and higher than that of GHRH. The GH-releasing activity of GHRPs is synergistic with that of GHRH, is not affected by opioid receptor antagonists, such as naloxone, and is only blunted by inhibitory influences, including neurotransmitters, glucose, free fatty acids, gluco corticoids, recombinant human GH and even exogenous somatostatin, which are known to almost abolish the effect of GHRH. GHRPs maintain their GH-releasing effect in somatotrope hypersecretory states such as in acromegaly, anorexia nervosa and hyperthyroidism. On the other hand, their good GH-releasing activity has been shown in some but not in other somatotrope hyposecretory states. In fact, reduced GH responses after GHRP administration have been reported in idiopathic GH deficiency as well as in idiopathic short stature, in obesity and in hypothyroidism, while in patients with pituitary stalk disconnection or Cushing's syndrome the somatotrope responsiveness to GHRPs is almost absent. In short children an increase in height velocity has also been reported during chronic GHRP treatment. Thus, based on their marked GH-releasing effect even after oral administration, GHRPs offer their own clinical usefulness for treatment of some GH hyposecretory states.
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PMID:Growth hormone-releasing peptides. 918 61

Growth hormone-releasing peptides (GHRPs) are a series of hepta (GHRP-1)- and hexapeptides (GHRP-2, GHRP-6, Hexarelin) that have been shown to be effective releasers of GH in animals and humans. More recently, a series of nonpeptidyl GH secretagogues (L-692,429, L-692,585, MK-0677) were discovered using GHRP-6 as a template. Some cyclic peptides as well as penta-, tetra-, and pseudotripeptides have also been described. This review summarizes recent developments in our understanding of the GHRPs, as well as the current nonpeptide pharmacologic analogs. GHRPs and their analogs have no structural homology with GHRH and act via specific receptors present at either the pituitary or the hypothalamic level. The GHRP receptor has recently been cloned and it does not show sequence homology with other G-protein-coupled receptors known so far. This evidence strongly suggests the existence of a natural GHRP-like ligand which, however, has not yet been found. Although the exact mechanism of action of GHRPs has not been fully established, there is probably a dual site of action on both the pituitary and the hypothalamus, possibly involving regulatory factors in addition to GHRH and somatostatin. Moreover, the possibility that GHRPs act via an unknown hypothalamic factor (U factor) is still open. The marked GH-releasing activity of GHRPs is reproducible and dose-related after intravenous, subcutaneous, intranasal, and even oral administration. The GH-releasing effect of GHRPs is the same in both sexes, but undergoes age-related variations. It increases from birth to puberty and decreases in aging. The GH-releasing activity of GHRPs is synergistic with that of GHRH and not affected by opioid receptor antagonists, while it is only blunted by inhibitory influences that are known to nearly abolish the effect of GHRH, such as neurotransmitters, glucose, free fatty acids, glucocorticoids, rhGH, and even exogenous somatostatin. GHRPs maintain their GH-releasing effect in somatotrope hypersecretory states, such as acromegaly, anorexia nervosa, and hyperthyroidism. On the other hand, GHRPs and their analogs have been reported to be effective in idiopathic short stature, in some situations of GH deficiency, in obesity, and in hypothyroidism, while in patients with pituitary stalk disconnection and in Cushing's syndrome the somatotrope responsiveness to GHRPs is almost absent. A potential role in the treatment of short stature, aging, catabolic states, and dilated cardiomyopathy has been envisaged.
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PMID:Growth hormone-releasing peptides and their analogs. 946 89

The G protein Go is highly expressed in neurons and mediates effects of a group of rhodopsin-like receptors that includes the opioid, alpha2-adrenergic, M2 muscarinic, and somatostatin receptors. In vitro, Go is also activated by growth cone-associated protein of Mr 43,000 (GAP43) and the Alzheimer amyloid precursor protein, but it is not known whether this occurs in intact cells. To learn about the roles that Go may play in intact cells and whole body homeostasis, we disrupted the gene encoding the alpha subunits of Go in embryonic stem cells and derived Go-deficient mice. Mice with a disrupted alphao gene (alphao-/- mice) lived but had an average half-life of only about 7 weeks. No Goalpha was detectable in homogenates of alphao-/- mice by ADP-ribosylation with pertussis toxin. At the cellular level, inhibition of cardiac adenylyl cyclase by carbachol (50-55% at saturation) was unaffected, but inhibition of Ca2+ channel currents by opioid receptor agonist in dorsal root ganglion cells was decreased by 30%, and in 25% of the alphao-/- cells examined, the Ca2+ channel was activated at voltages that were 13.3 +/- 1.7 mV lower than in their counterparts. Loss of alphao was not accompanied by appearance of significant amounts of active free betagamma dimers (prepulse test). At the level of the living animal, Go-deficient mice are hyperalgesic (hot-plate test) and display a severe motor control impairment (falling from rotarods and 1-inch wide beams). In spite of this deficiency, alphao-/- mice are hyperactive and exhibit a turning behavior that has them running in circles for hours on end, both in cages and in open-field tests. Except for one, all alphao-/- mice turned only counterclockwise. These findings indicate that Go plays a major role in motor control, in motor behavior, and in pain perception and also predict involvement of Go in Ca2+ channel regulation by an unknown mechanism.
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PMID:Multiple neurological abnormalities in mice deficient in the G protein Go. 950 Dec 52

The effect of testicular administration of peptides synthesized in the testis (somatostatin, oxytocin) or peptide antagonists (opioid receptor antagonists naloxone, nalmefene, anti-corticotrop hormone-releasing hormone antiserum, beta-endorphin antiserum), partial denervation of the testis, and combination of local treatment with peptides/peptide antagonists and denervation was studied on testicular steroidogenesis in immature hemicastrated rats. The observations indicate that beta-endorphin, corticotrop hormone-releasing hormone, oxytocin, and somatostatin exert a stimulatory, whereas enkephalin has an inhibitory action on steroidogenesis. Surgical (vasectomy) or pharmacological (local injection of 6-hydroxydoparnine) denervation suppresses testosterone secretion. Following partial denervation of the testis the effect of naloxone or oxytocin on steroidogenesis observed in fully innervated gonad is not present or the effect is paradoxical. These results indicate that steroidogenesis is fine-tuned by local peptide actions, and neural inputs. Data further suggest an interaction between local peptide action and neural control.
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PMID:Fine-tuning control of testicular functions. 950 81

The mu-opioid receptor has recently been shown to stimulate phosphoinositide-specific phospholipase C via the pertussis toxin-sensitive G16 protein. Given the promiscuous nature of G16 and the high degree of resemblance of signaling properties of the three opioid receptors, both delta- and kappa-opioid receptors are likely to activate G16. Interactions of delta- and kappa-opioid receptors with G16 were examined by coexpressing the opioid receptors and G alpha16 in COS-7 cells. The delta-selective agonist [D-Pen2,D-Pen5] enkephalin potently stimulated the formation of inositol phosphates in cells coexpressing the delta-opioid receptor and G alpha16. The delta-opioid receptor-mediated stimulation of phospholipase C was absolutely dependent on the coexpression of G alpha16 and exhibited appropriate ligand selectivity and dose dependency. Similar transfection studies revealed only weak stimulation by the mu-opioid receptor, whereas the kappa-opioid receptor produced moderate phospholipase C activity. G alpha16 thus appeared to interact differentially with the three opioid receptors. Radioligand binding assays indicate that the mu-opioid receptor was expressed at a lower level than those of the delta- and kappa-opioid receptors. To examine if differential coupling to G alpha16 is prevalent, a panel of Gs- or Gi-coupled receptors was coexpressed with G alpha16 in COS-7 cells and assayed for agonist-induced stimulation of phospholipase C. Activation of alpha2- and beta2-adrenergic, dopamine D1 and D2, adenosine A1, somatostatin-1 and -2, C5a, formyl peptide, and luteinizing hormone receptors all resulted in stimulation of phospholipase C, with maximal stimulations ranging from 1.5- to almost 17-fold. These findings suggest that the promiscuous G alpha16 can in fact discriminate among different receptors and that such preferential interaction might in part be due to the abundance of receptors.
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PMID:Differential coupling of mu-, delta-, and kappa-opioid receptors to G alpha16-mediated stimulation of phospholipase C. 957 9

In NG108-15 cells inhibition of both N-type calcium channel current and adenylyl cyclase by somatostatin (SRIF) was not sustained but rapidly desensitized in the continued presence of the drug. The degree and rate of desensitization were concentration-dependent, and the desensitization was homologous with respect to the delta-opioid receptor. We have been unable to obtain evidence for the involvement of G protein-coupled receptor kinases (GRKs) in this desensitization. SRIF-induced desensitization of N-type calcium channel currents was not reduced in cells stably overexpressing a dominant negative mutant of GRK2 or following intracellular dialysis with GRK2- and GRK3-blocking peptides or with heparin. Inhibitors of protein kinase A, protein kinase C, and protein kinase G were also without effect. In contrast, both the rate and degree of SRIF-induced desensitization were reduced by pretreatment with phenylarsine oxide or concanavalin A, both inhibitors of receptor endocytosis. Furthermore, SRIF-induced desensitization was enhanced by monensin, which prevents receptor recycling back to the plasma membrane. Similarly, SRIF-induced desensitization of adenylyl cyclase inhibition was not reduced in cells stably overexpressing dominant negative mutant GRK2 but was reduced in cells pretreated with the receptor endocytosis inhibitor hyperosmotic sucrose or concanavalin A. These data are consistent with the view that SRIF-induced desensitization in NG108-15 cells results from receptor internalization.
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PMID:Somatostatin receptor desensitization in NG108-15 cells. A consequence of receptor sequestration. 983 85

Intrathecal administration of octreotide, a stable somatostatin analogue, provides pain relief in patients, and locally applied somatostatin inhibits firing of nociceptive dorsal horn neurons. In the present study, we have raised polyclonal antibodies that specifically detect the somatostatin receptor sst2A and used these antisera for immunocytochemical localization of the receptor protein in the rat spinal cord and dorsal root ganglia. In the superficial layers of the dorsal horn, sst2A-like immunoreactivity (Li) formed a dense network consisting of neuronal perikarya and dendrites which were often closely apposed by, but not co-contained within, somatostatin-14-immunoreactive nerve fibres and terminals. sst2A-Li was resistant to dorsal rhizotomy and did not colocalize with either substance P or calcitonin gene-related peptide suggesting that sst2A-Li was not located to primary afferents, but rather confined to second-order spinal neurons. The position of sst2A-Li perikarya and dendrites in the dorsal horn appeared to be similar to those containing mu-opioid receptor-Li; however, double labelling experiments revealed no instances of coexistence of these two receptors. sst2A-Li was also observed in the dorsal root ganglia predominantly targeted to the somatic plasmalemma of medium size neurons distinct from those expressing somatostatin-14 or delta-opioid receptors. Thus, the present results not only provide a morphological substrate for spinal octreotide analgesia but also show that somatostatin and opioids are poised to modulate nociceptive transmission by distinct anatomical systems.
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PMID:Immunocytochemical localization of somatostatin receptor sst2A in the rat spinal cord and dorsal root ganglia. 987 49

In slices of human neocortex, prelabelled with [3H]-choline, the release of [3H]-acetylcholine reflects the evoked release of endogenous acetylcholine which was elicited by the same electrical stimulation paradigm. [3H]-Acetylcholine release was depressed by the delta-opioid receptor agonist D-Pen2-D-Pen5-enkephalin. When the nerve endings were depolarized by elevating extracellular potassium the evoked [3H]-acetylcholine release was similarly depressed by D-Pen2-D-Pen5-enkephalin in the absence, but not in the presence, of tetrodotoxin which blocks action potential propagation. Therefore, the delta-opioid receptor inhibiting [3H]-acetylcholine release should not be located to cholinergic nerve terminals, but rather to interneurons. The somatostatin2 receptor partial agonist octreotide per se did not influence action potential-evoked [3H]-acetylcholine release, but prevented the inhibition of release of [3H]-acetylcholine by D-Pen2-D-Pen5-enkephalin. Similarly, the delta 1-opioid receptor antagonist 7-benzylidenenaltrexon per se did not influence [3H]-acetylcholine release, but prevented of the inhibition of release by D-Pen2-D-Pen5-enkephalin. From the present findings we conclude: (1) The evoked release of [3H]-acetylcholine from human neocortex slices reflects the release of endogenous acetylcholine. (2) It is inhibited in an indirect manner by opioid receptors of the delta 1-subtype, which (3) are not localized on cholinergic axon terminals but on soma and dendrites of somatostatin-containing interneurons, where they inhibit somatostatin release. (4) These interneurons innervate cholinergic nerve endings in the human neocortex and appear to facilitate acetylcholine release via somatostatin2 receptors.
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PMID:delta 1-Opioid receptor-mediated control of acetylcholine (ACh) release in human neocortex slices. 1019 26

Sendide, a tachykinin NK1 receptor antagonist, was tested for antagonism against scratching, biting and licking responses elicited by intrathecal (i.t.) injections of various tachykinin receptor agonists, N-methyl-D-aspartate (NMDA), somatostatin and bombesin, in mice. Tachykinin NK1 receptor agonists, substance P, physalaemin and septide, produced a characteristic behavioural response, consisting of scratching, biting and licking. The substance P-induced response was reduced by small doses (0.0625-1.0 pmol) of sendide in a dose-dependent manner. The behavioural response elicited by other tachykinin NK1 receptor agonists, physalaemin and septide, was also reduced significantly by a small dose (1.0 pmol) of sendide. The inhibitory effect of sendide (1.0 pmol) was not affected by pretreatment with the opioid receptor antagonist, naloxone, at doses up to 4.0 mg/kg. Higher doses of sendide were needed to reduce the behavioural response to neurokinin A, a tachykinin NK2 receptor agonist, neurokinin B, a tachykinin NK3 receptor agonist and eledoisin, a tachykinin NK2/NK3 receptor agonist. Pretreatment with naloxone (2.0 mg/kg, i.p.) significantly antagonized sendide (1024 pmol)-induced inhibition of the behavioural responses to neurokinin A, neurokinin B and eledoisin. The behaviours elicited by i.t. injection of NMDA, somatostatin or bombesin were also reduced by a higher dose (1024 pmol) of sendide and this sendide effect was reversed by naloxone. These findings suggest that sendide at higher doses may possess opioid activity in addition to an antagonistic action at tachykinin NK1 receptors in the spinal cord.
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PMID:Opioid activity of sendide, a tachykinin NK1 receptor antagonist. 1022 61


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