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)

1. In rat pituitary tumour cells (GC cells), spontaneous oscillations of the intracellular concentration of Ca2+ ([Ca2+]i) induce growth hormone (GH) secretion that is inhibited by octreotide, a somatostatin (SRIF) agonist which binds to SRIF subtype (sst) receptor 2. The effects of its functional activation on the control of [Ca2+]i were investigated using fluorimetric measurements of [Ca2+]i. 2. SRIF decreases the basal [Ca2+]i and the [Ca2+]i rise in response to forskolin (FSK) through the inhibition of L-type voltage-dependent Ca2+ channels. 3. Pretreatment with octreotide or with L-Tyr8++ Cyanamid 154806, a sst2 receptor antagonist, abolishes the SRIF-induced inhibition of [Ca2+]i. Octreotide is known to operate through agonist-induced desensitization, while the antagonist operates through receptor blockade. 4. sst1 and sst2 receptor-immunoreactivities (-IRs) are localized to cell membranes. sst2, but not sst1 receptor-IR, internalizes after cell exposure to octreotide. 5. SRIF-induced inhibition of basal [Ca2+]i or FSK-induced Ca2+ entry is blocked by pertussis toxin (PTX). 6. FSK-induced cyclic AMP accumulation is only partially decreased by SRIF or octreotide, indicating that sst2 receptors are coupled to intracellular pathways other than adenylyl cyclase (AC) inhibition. 7. In the presence of H-89, an inhibitor of cyclic AMP-dependent protein kinase (PKA), SRIF-induced inhibition of basal [Ca2+]i is still present, although reduced in amplitude. 8. SRIF inhibits [Ca2+]i by activating sst2 receptors. Inhibition of AC activity is only partly responsible for this effect, and other transduction pathways may be involved.
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PMID:Somatostatin-induced control of cytosolic free calcium in pituitary tumour cells. 1071 45

The mouse somatostatin (somatotropin release inhibiting factor, SRIF) sst(5) receptor coding sequence was cloned from a mouse BALB/c genomic library. It shows 97% and 81% homology with the corresponding rat and human receptors, respectively. The msst(5) receptor messenger RNA (mRNA) is present at low levels in the adult mouse brain, with significant expression in a few nuclei only, e.g. in the septum (lateral septal nuclei) or the amygdala (medial amygdaloid nucleus); very few signals were observed in the mesencephalon, metencephalon, and myelencephalon (except the dorsal motor nucleus of the vagus nerve). The msst(5) receptor was stably expressed in the hamster fibroblast cell line CCL39-SRE-Luci, which harbours the luciferase reporter gene driven by the serum responsive element. [(125)I]LTT-SRIF-28 ([Leu(8), D-Trp(22), (125)I-Tyr(25)]-SRIF-28), [(125)I]Tyr(10)-CST, [(125)I]CGP 23996, and [(125)I]Tyr(3)-octreotide labelled msst(5) receptors with high affinity (pK(d) values: 11.0, 10.15, 9.75 and 9.43) and in a saturable manner, but defined different Bmax values: 697, 495, 540 and 144 fmoles/mg, respectively. [(125)I]LTT-SRIF-28-labelled sites displayed the following rank order: SRIF-28> rCST-14> somatuline > CGP-23996= SRIF-14= octreotide, whereas [(125)I]Tyr(3)-octreotide-labelled sites displayed a different profile: octreotide > SRIF-28> rCST-14= somatuline > SRIF-14> CGP-23996. The pharmacological profiles determined with [(125)I]LTT-SRIF-28, [(125)I]CGP 23996 and [(125)I]Tyr(10)-CST correlated highly significantly (r(2) =0.88-0.99), whereas [(125)I]Tyr(3)-octreotide binding was rather divergent (r(2) =0.77). Also, human and mouse sst(5) receptor profiles are very different, e. g. r(2) =0.385 for [(125)I]Tyr(10)-CST and r(2) =0.323 for [(125)I]LTT-SRIF-28-labelled sites. Somatostatin induces expression of luciferase reporter gene in CCL39-SRE-Luci cells. The profile was consistent with a msst(5) receptor-mediated effect although apparent potency in the luciferase assay was much reduced compared to radioligand binding data: Octreotide = SRIF-28> rCST-14= SRIF-14= CGP-23996. Octreotide, SRIF-28, BIM23052 and D Tyr Cyanamid 154806 behaved as full or nearly full agonists in comparison to SRIF-14, whereas the other compounds had relative efficacies of 40 to 70%. The present study shows that agonists radioligands define apparently different receptor populations in terms of number of sites and pharmacological profile in cells expressing a single recombinant receptor. These variations suggest that the conformation of the ligand receptor complex may vary depending on the agonist. Further, the msst(5) receptor, although primarily coupled to Gi/Go proteins, is able to stimulate luciferase gene expression driven by the serum responsive element. Finally, it is suggested that putative sst(2) selective agonists e.g. octreotide, RC160 or BIM23027 show similar or higher potency at msst(5) receptors than SRIF-14.
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PMID:Cloning, expression and pharmacological characterisation of the mouse somatostatin sst(5) receptor. 1081 61

N-methyl-D-aspartate (NMDA) receptors exist on noradrenergic axon terminals and mediate enhancement of noradrenaline (NA) release. We here investigated modulation by somatostatin (SRIF, somatotropin release inhibiting factor) of the NMDA-induced release of NA using superfused hippocampal synaptosomes. The NMDA response was increased by SRIF-28 and SRIF-14, but not SRIF-28((1 - 14)), whereas the release of [(3)H]-NA elicited by alpha-amino-3-hydroxy-5-methylisoxazide-4-propionic acid (AMPA) was unaffected. SRIF-14 did not mimic glycine at the NMDA receptor but activated SRIF receptors sited on noradrenergic terminals. The SRIF-14 effect was blocked by pertussis toxin but mimicked by mastoparan, a G-protein activator. BIM-23056, but not Cyanamid 154806, antagonized the SRIF-14 effect. This effect was mimicked by L362855, a partial agonist at the sst(5) subtype, but not by the new selective sst(1) - sst(4) receptor agonists L797591, L779976, L796778 and L803087. Protein kinase C (PKC) inhibitors (H7, staurosporine, GF 209103X, cheleritrine and sphingosine) prevented the SRIF-14 effect, while phorbol 12-myristate 13-acetate enhanced the NMDA response. SRIF-14 permitted NMDA receptor activation in the presence of 1.2 mM Mg(2+) ions, both in hippocampal synaptosomes and slices. Blockade of inositol-1,4,5-trisphosphate (InsP(3)) receptors with heparin abolished the effect of SRIF-14. It is concluded that SRIF receptors, possibly of the sst(5) subtype, can exert a permissive role on NMDA receptors colocalized on hippocampal noradrenergic terminals: activation of sst(5) receptors is coupled to pertussis toxin-sensitive G proteins enhancing phosphoinositide metabolism with activation of InsP(3) receptors and PKC; NMDA receptor subunits might be phosphorylated with consequent removal of the Mg(2+) block in absence of depolarization.
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PMID:Somatostatin potentiates NMDA receptor function via activation of InsP(3) receptors and PKC leading to removal of the Mg(2+) block without depolarization. 1082 83

Somatostatin (somatotropin release-inhibiting factor, SRIF) receptor subtypes are expressed by several retinal neurons, suggesting that SRIF acts at multiple levels of the retinal circuitry, although functional data on this issue are scarce. Of the SRIF receptors, the sst2A isoform is expressed by rod bipolar cells (RBCs) of the rabbit retina, and in isolated RBCs we studied the role of sst2 receptors in modulating both K+ current (IK) and the intracellular free [Ca2+] ([Ca2+]i) using both voltage-clamp and Ca2+-imaging techniques. SRIF and octreotide (a SRIF agonist that binds to sst2 receptors) inhibited that component of IK corresponding to the activation of large-conductance, Ca2+- and voltage-dependent K+ channels (IBK) and reduced the K+-induced [Ca2+]i accumulation, suggesting that SRIF effects on IBK may have been secondary to inhibition of Ca2+ channels. Octreotide effects on IBK or on [Ca2+]i accumulation were prevented by RBC treatment with L-Tyr8-Cyanamid 154806, a novel sst2 receptor antagonist, indicating that SRIF effects were mediated by sst2 receptor activation. The present data indicate that SRIF may modulate the information flow through second-order retinal neurons via an action predominantly at sst2 receptors, contribute to the proposition that SRIF be added to the growing list of retinal neuromodulators, and suggest that one of its possible roles in the retina is to regulate transmitter release from RBCs.
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PMID:Modulation of potassium current and calcium influx by somatostatin in rod bipolar cells isolated from the rabbit retina via sst2 receptors. 1141 63

The effects of somatostatin (SRIF, somatotropin release inhibiting factor) on the release of glutamate have been investigated using superfused mouse cerebrocortical synaptosomes. SRIF-14 inhibited the K+ (12 mM)-evoked overflow of preaccumulated [3H]D-aspartate as well as that of endogenous glutamate. Cyanamid 154806, a selective sst2 receptor antagonist, but not BIM-23056, an antagonist at sst5 receptors, prevented the SRIF-14 effect. Octreotide and L779976, selective agonists at sst2 receptors, mimicked SRIF-14, whereas L797591, L796778, L803087 and L362855, selective agonists at sst1, sst3, sst4 and sst5 receptor subtypes, were inactive. Activation of sst2 receptors seems to involve inhibition of the adenylyl cyclase-protein kinase A pathway present in glutamatergic terminals since the adenylyl cyclase inhibitor MDL-12,330A and the protein kinase A inhibitor H89 prevented the K+-evoked [3H]D-aspartate overflow. Consistent with the involvement of adenylyl cyclase, depolarization with 12 mM K+ increased synaptosomal cyclic AMP (cAMP) content, while forskolin, an adenylyl cyclase activator, potentiated basal [3H]D-aspartate release in an octreotide-, MDL-12,330A- and H89-sensitive manner. To conclude, glutamatergic cerebrocortical nerve endings possess release-inhibiting sst2 receptors which represent potential targets for new drugs able to mitigate the effects of excessive glutamate transmission.
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PMID:Somatostatin inhibits glutamate release from mouse cerebrocortical nerve endings through presynaptic sst2 receptors linked to the adenylyl cyclase-protein kinase A pathway. 1497 94

The aim of the present study is to investigate the effect of somatostatin (SST). It is well known that SST is a neuromodulator in the central nervous system and is involved in the regulation of metabolic and neuroendocrine functions. Recent experimental and clinical findings indicate a role for SST in the central processing of nociception. Therefore, we tested the hypothesis whether a local release of SST modulates the tooth-pulp (TP)-evoked upper cervical spinal dorsal horn (C(1)) neuronal activity, using microiontophoretic application and immunohistochemical techniques. Extracelluar single unit recordings were made from 35 C(1) neurons responding to TP electrical stimulation (TPS) in pentobarbital anesthetized rats. Microiontophoretic application of SST (30-70 nA) current dependently inhibited TP-evoked C(1) neuronal discharges (60%, 21/35). The inhibition of this discharge by 50 nA SST application was abolished by co-application of a SST(2) receptor antagonist (Cyanamid-154806, 50 nA). Immunoreactivity for SST(2A) receptor was found in the superficial layer (Iota-IotaIotaIota) of C(1) dorsal horn. These results suggest that a local release of SST modulates the TP-evoked C(1) neuronal activity and this may contribute to a useful therapeutic target for the alleviation of tooth pain and trigeminal hyperalgesia.
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PMID:Somatostatin inhibits tooth-pulp-evoked rat cervical dorsal horn neuronal activity. 1818 72

Somatostatin acts at five G protein-coupled receptors, sst(1)-sst(5). In mouse ischaemic retinas, the over-expression of sst(2) (as in sst(1) knock-out mice) results in the reduction of cell death and glutamate release. In this study, we reported that, in wild-type retinas, somatostatin, the multireceptor ligand pasireotide and the sst(2) agonist octreotide decreased ischaemia-induced cell death and that octreotide also decreased glutamate release. In contrast, cell death was increased by blocking sst(2) with cyanamide. In sst(2) over-expressing ischaemic retinas, somatostatin analogues increased cell death, and octreotide also increased glutamate release. To explain this reversal of the anti-ischaemic effect of somatostatin agonists in the presence of sst(2) over-expression, we tested sst(2) desensitisation because of internalisation or altered receptor function. We observed that (i) sst(2) was not internalised, (ii) among G protein-coupled receptor kinases (GRKs) and regulators of G protein signalling (RGSs), GRK1 and RGS1 expression increased following ischaemia, (iii) both GRK1 and RGS1 were down-regulated by octreotide in wild-type ischaemic retinas, (iv) octreotide down-regulated GRK1 but not RGS1 in sst(2) over-expressing ischaemic retinas. These results demonstrate that sst(2) activation protects against retinal ischaemia. However, in the presence of sst(2) over-expression sst(2) is functionally desensitised by agonists, possibly because of sustained RGS1 levels.
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PMID:Modulation of the neuronal response to ischaemia by somatostatin analogues in wild-type and knock-out mouse retinas. 1862 22

A recent in vitro electrophysiological analysis combined with anatomical approach suggests that a potential disinhibitory mechanism involving somatostatin (SST), which is released by interneurons in the superficial dorsal horn, contributes to nociceptive transmission (Yasaka et al., 2010); however, whether this mechanism occurs in vivo remains to be determined. The aim of the present study was to investigate whether iontophoretic application of SST facilitates the excitability of nociceptive upper cervical spinal dorsal horn (C1) neurons through GABAergic disinhibiton, using extracellular electrophysiological recording with multibarrel electrodes and immunohistochemical techniques. Immunoreactivity of SST2A receptors was found in layer II of the C1 dorsal horn in the rat and most of these neurons co-expressed the GABA synthesizing enzyme glutamate decarboxylase 67. Single-unit recordings were made from C1 neurons responding to tooth-pulp (TP) electrical stimulation in pentobarbital anesthestized rats. Iontophoretic application of SST significantly increased TP-evoked C1 neuronal discharges in layers I and II of the spinal dorsal horn and this effect occurred in a current-dependent manner. The facilitation of this discharge by SST application was abolished with co-application of the SST2 receptor antagonist, Cyanamid 154806. Iontophoretic application of GABAA receptor antagonist, bicuculline, induced facilitation of TP-evoked C1 neuronal discharges. There was no significant difference in the relative number of spikes between SST and bicuculline applications. These results suggest that a local release of SST facilitates the excitability of trigeminal nocicepitve C1 neuronal activity via inhibition of GABAergic neurons. Therefore, SST2A receptors expressed in layer II GABAergic inhibitory interneurons play an important role in trigeminal nociceptive transmission and are a potential therapeutic target in the treatment of trigeminal pain, including hyperalgesia.
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PMID:Somatostatin enhances tooth-pulp-evoked cervical dorsal horn neuronal activity in the rat via inhibition of GABAergic interneurons. 2432 30

Allatostatin C is the arthropod homolog of vertebrate somatostatin. The gene went through a local gene triplification leading to the existence of three genes coding such peptides, allatostatins C, CC and CCC. All three genes are still present in several chelicerates, such as the horseshoe crab Limulus polyphemus, several spiders and the scorpion Mesobuthus martensii, the myriapod Strigamia maritima, as well as at least two insect species, Locusta migratoria and Athalia rosae, a sawfly. All three peptides have well conserved primary structures and peptides can easily be classified as either allatostatin C, CC or CCC. In most insect species only two of the genes have been preserved. In many species, these are CC and CCC, but in Diptera, Lepidoptera and Coleoptera it are allatostatins C and CC that are still present. In some arthropod species two or even all three genes can still be found closely associated in the genome and are present on the same scaffold showing that a local amplification was at the origin of these genes.
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PMID:Allatostatins C, double C and triple C, the result of a local gene triplication in an ancestral arthropod. 2710 37