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)

Somatostatin (SOM) exists in at least two active forms in the central nervous system (CNS): SOM-14 and SOM-28. These peptides have multiple actions on neurons in the CNS and these actions appear to be mediated by different receptors. Thus, SOM-14 can enhance voltage-dependent K currents, whereas SOM-28 inhibits these same currents, sometimes even in the same neurons. These effects are not mediated via cAMP, but do seem mediated by GTP-binding proteins. On the other hand, both forms of SOM inhibit a voltage-dependent Ca current, again via a GTP-binding protein. SOM can also interact with the GABA(A) receptor to modulate responses to this inhibitory transmitter. The physiological effects of SOM in an integrated circuit within the CNS will depend on the form of SOM released, the kinds and numbers of receptors present on the postsynaptic neurons, and the presence of other neurotransmitters.
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PMID:Electrophysiological effects of somatostatin-14 and somatostatin-28 on mammalian central nervous system neurons. 197 25

Functional interactions between gamma-aminobutyric acid (GABA) and somatostatin are suggested by the presence of synaptic contacts between GABA and somatostatin neurons, colocalisation of GABA and somatostatin and reciprocal modulation of somatostatin and GABA release. Nevertheless, a direct interaction of somatostatin with the GABA(A) receptor complex has not yet been investigated. A quantitative autoradiographic technique was used to determine the ability of somatostatin to interact with the [35S]t-butylbicyclophosphothionate [35S]TBPS binding sites of the GABA(A) receptor complex: somatostatin inhibited [35S]TBPS binding with IC50 values in the micromolar range in all brain regions studied. These results demonstrate for the first time a direct interaction between somatostatin and the GABA(A) receptor complex.
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PMID:A novel recognition site for somatostatin-14 on the GABA(A) receptor complex. 957 Apr 56

Immunocytochemical and autoradiographic methods were used to localize the GABA(B) receptor in the normal rat hippocampus. GABA(B) receptor 1-like immunoreactivity (GBR1-LI) was most intense in presumed GABAergic interneurons of all hippocampal subregions. It was also present throughout the hippocampal neuropil, where it was most intense in the dendritic strata of the dentate gyrus, which are innervated by the perforant pathway and inhibitory dentate hilar cells, and in strata oriens and radiatum of area CA3. The dendritic regions of area CA1 exhibited less GBR1-LI than area CA3. GBR1-LI was detectable in the somata of CA1 pyramidal cells, but was minimal or undetectable within the somata of dentate granule cells and CA3 pyramidal cells. GBR1-LI was similarly minimal in the dentate hilar neuropil, and in stratum lucidum, the two regions that contain granule cell axons and terminals. Nor was GBR1-LI detectable in the inhibitory basket cell fiber systems that surround hippocampal principal cell somata. Fluorescence co-localization studies indicated that significant proportions of interneurons expressing somatostatin, neuropeptide Y, cholecystokinin, calbindin, or calretinin also expressed GBR1-LI constitutively. Conversely, parvalbumin-positive GABAergic basket cells of the dentate gyrus and hippocampus, which form GABA(A) receptor-mediated inhibitory axo-somatic synapses, rarely contained detectable GBR1-LI. High resolution autoradiography with the GABA(B) receptor antagonist CGP 62349 revealed a close correspondence between receptor ligand binding and GBR1-LI, with several notable exceptions. Ligand binding closely matched GBR1-LI throughout the hippocampal, cortical, thalamic, and cerebellar neuropil. However, the hippocampal interneuron somata and dendrites that exhibited the most intense GBR1-LI, and the GBR1-positive somata of CA1 pyramidal cells, did not exhibit a similar density of [3H]-CGP 62349 binding. These data clarify the relationship between immunocytochemically identified receptor protein and potentially functional receptors, indicating that GBR1-LI reflects both non-functional cytoplasmic GBR1 and the ligand-bindable form of the protein, both before dimerization with GBR2 and after translocation to functional sites within cells. The staining and binding patterns further suggest that GBR1 is constitutively expressed in specific neuronal populations, and may exist in higher concentration in the axons of inhibitory hippocampal pathways that innervate dendritic zones, than in axo-somatic inhibitory terminals. Whether GBR1 is inducible in cells that contain GBR1 mRNA, but no detectable constitutive protein, remains to be determined in experimental studies.
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PMID:Localization of GABA(B) (R1) receptors in the rat hippocampus by immunocytochemistry and high resolution autoradiography, with specific reference to its localization in identified hippocampal interneuron subpopulations. 1058 87

The biosynthesis and secretion of somatostatin (SRIH) within the hypothalamic periventricular-median eminence (PeN-ME) pathway follows a sexually differentiated developmental pattern beginning in the early neonatal period. It is generally accepted that testosterone plays a role in these processes, but the mechanisms underlying the age and sex differences are poorly understood. The present study sought to investigate the hypothesis that gamma-aminobutyric acid (GABA) may play a role in determining sex differences in SRIH neuronal activity. Using an in vitro hypothalamic preparation where more than 97% of the immunoreactive SRIH is contained within the PeN-ME pathway, peptide release in response to the GABA(A) receptor antagonist, bicuculline, was followed through development. In the male a stimulatory response, indicative of an inhibitory GABAergic tone on SRIH secretion, was observed as early as postnatal day (P) 5. This persisted throughout juvenile development (P10, P17) and was present also in the adult male (P75), but in the peripubertal period the response to bicuculline was first lost (P25) and then reversed to an inhibition (P40), suggesting a transient switch to an apparent stimulatory GABAergic tone on SRIH release. By contrast, in the female, no bicuculline responsiveness was seen until P25 when it caused a decrease in SRIH release which persisted into adulthood. Using in situ hybridization studies we found no evidence to support the view that these age- and sex-dependent differences were due to changes in the expression of GABA(A) receptor alpha-subunits (alpha(1) and alpha(2)) which are colocalised in the PeN SRIH neurons. Following adult gonadectomy, the bicuculline response was abolished in the male, whereas, in the female it was reversed and identical in magnitude to the response in the intact male. These results demonstrate marked sex differences in GABA(A)-receptor-mediated influences on SRIH release which develop soon after birth and, in the adult, depend on gonadal factors. In the male these factors activate a primarily inhibitory influence, whereas in the female they facilitate an apparently stimulatory tone of GABA on SRIH secretion via the GABA(A) receptor. Our findings thus support the view that GABAergic transmission may play a key role in generating sex differences in the mode of SRIH secretion from the hypothalamus which has been shown to be a major factor in determining the sexually dimorphic patterns of growth hormone secretion.
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PMID:Sexually dimorphic ontogeny of GABAergic influences on periventricular somatostatin neurons. 1065 31

Numerous reports in both humans and animals have confirmed that benzodiazepines produce amnesia; however, mechanisms mediating this effect are not clear. In view of the important role of brain somatostatin (SRIF) in the cognitive function of rats, this study sought to determine if the benzodiazepine, diazepam, alters somatostatinergic system in the rat frontoparietal cortex. Intraperitoneal (i.p.) administration of diazepam (5 mg/kg/day) to male Wistar rats (200-250 g) for 3 or 7 days decreased the number of SRIF receptors (26 and 37%, respectively) in synaptosomes from the frontoparietal cortex, without influencing their apparent affinity. This decrease in the tracer binding was not attributable to a direct effect of diazepam on SRIF receptors, because no decrease of SRIF binding was induced by a large concentration of diazepam (10(-4) M) when the drug was added to a preparation of synaptosomes from frontoparietal cortex of untreated rats. To determine if the effect of diazepam on SRIF binding is related to the binding of diazepam to its recognition site on the GABA(A) receptor, a benzodiazepine antagonist, 2-phenylpyrazolo[3,4-c]quinolin-3(5H)-one (CGS 8216) was administered before the diazepam injection. Pretreatment with CGS 8216 (20 mg/kg/day, i.p.) blocked completely the diazepam-induced decrease in the number of SRIF receptors. CGS 8216 alone had no observable effect. The decrease in the number of 125I-Tyr11-SRIF receptor induced by diazepam was accompanied by a decrease in the effect of SRIF, after 15 seconds of stimulation, on inositol 1,4, 5-trisphosphate (IP3) mass accumulation in the rat frontoparietal cortex at 3 (64%) or 7 days (59%) after its administration. Diazepam alone had no observable effect on mass accumulation of IP3. After 14 days of daily diazepam injections, the levels of binding of 125I-Tyr11-SRIF in the frontoparietal cortex returned to control values, coinciding with the tolerance that develops to this benzodiazepine agonists when administered chronically. The decrease in IP3 levels was still observed after 14 days (57%) diazepam administration. Diazepam and CGS 8216 did not affect SRIF-like immunoreactivity levels in the frontoparietal cortex at the three time intervals studied (3, 7 or 14 days). The alteration of frontoparietal cortex SRIF receptor-effector system after 3 or 7 days of diazepam treatment suggests that somatostatinergic neurotransmission plays a role in the mechanism of diazepam action on memory.
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PMID:Diazepam attenuation of somatostatin binding and effect of somatostatin on accumulation of inositol 1,4,5-trisphosphate in the rat frontoparietal cortex. 1088 44

Because GABA and its related enzymes have been determined in beta-cells of pancreas islets, effects of GABA on pancreatic exocrine secretion were investigated in the isolated, perfused rat pancreas. GABA, given intra-arterially at concentrations of 3, 10, 30, and 100 microM, did not exert any influence on spontaneous or secretin (12 pM)-induced pancreatic exocrine secretion. However, GABA further elevated CCK (10 pM)-, gastrin-releasing peptide (100 pM)-, or electrical field stimulation-induced pancreatic secretions of fluid and amylase dose dependently. The GABA (30 microM)-enhanced CCK-induced pancreatic secretions were completely blocked by bicuculline (10 microM), a GABA(A) receptor antagonist, but were not affected by saclofen (10 microM), a GABA(B) receptor antagonist. The enhancing effects of GABA (30 microM) on CCK-induced pancreatic secretions were not changed by tetrodotoxin (1 microM) but were partially reduced by cyclo-(7-aminoheptanonyl-Phe-D-Trp-Lys-Thr[BZL]) (10 nM), a somatostatin antagonist. In conclusion, GABA enhances pancreatic exocrine secretion induced by secretagogues, which predominantly induce enzyme secretion, via GABA(A) receptors in the rat pancreas. The enhancing effect of GABA is partially mediated by inhibition of islet somatostatin release.
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PMID:Effects of gamma-aminobutyric acid on secretagogue-induced exocrine secretion of isolated, perfused rat pancreas. 1100 53

1. This autoradiographic study was conducted to investigate somatostatin modulation of GABA(A) receptor binding in hypothalamic structures of immobilization-stressed rats. 2. GABA(A) receptor binding was labelled with [35S]-t- butylbicyclophosphorothionate (TBPS), which binds in or near the chloride channel. 3. Several structures of the rat hypothalamus (i.e. the peri- and paraventricular nuclei) display an increase in [35S]-TBPS binding as well as an alteration of the modulatory effect of somatostatin on the GABA(A) receptor complex under stress. Furthermore, these results demonstrate for the first time that somatostatin is particularly effective in modifying [35S]-TBPS binding to the GABA(A) receptor in rat hypothalamus.
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PMID:Allosteric modulation of the GABA(A) receptor in rat hypothalamus by somatostatin is altered by stress. 1125 49

1. The present study was designed to assess the effect of the tetradecapeptide somatostatin on the GABA(A) receptor complex in the rat hypothalamus. 2. GABA(A) receptors were labelled with [35S]-tert-butylbicyclophosphorothionate (TBPS), which binds in or near the chloride channel, and binding as assessed by in vitro quantitative autoradiography using a computer-assisted image analysis system. 3. Somatostatin inhibited the binding of [35S]-TBPS to the convulsant site of the hypothalamic GABA(A) receptor complex of rat slide-mounted hypothalamic structures in a concentration-dependent manner with an affinity in the micromolar range (10(-6) to 3 x 10(-6) mol/L). Somatostatin appeared to mimic the effects of the neurosteroid 5alpha-pregnane-3alpha ol-one (5alpha3alphaP), GABA and picrotoxin on [35S]-TBPS binding in the rat hypothalamus in all structures examined. Furthermore, GABA or muscimol (a GABA(A) receptor agonist), when added to the incubation medium, enhanced the capacity of somatostatin to inhibit [35S]-TBPS binding, with an IC50 of 10(-7) mol/L. However, incubation with bicuculline (a GABA(A) receptor antagonist) led to the abolition of the inhibitory effect of somatostatin on [35S]-TBPS specific binding in rat hypothalamus. 4. The present results demonstrate the presence of a modulatory effect of somatostatin on the GABA(A) receptor complex in rat hypothalamic structures. Furthermore, the data suggest that somatostatin allosterically modifies [35S]-TBPS binding through a mechanism similar to that of GABA. Taken together, these results provide evidence for the presence of somatostatin- GABA interactions in rat hypothalamus.
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PMID:Modulation Of [35S]-tert-butylbicyclophosphorothionate binding by somatostatin in rat hypothalamus. 1198 38

Gonadal steroids exert an important regulatory influence upon the biosynthetic and secretory activity of the somatostatin and growth hormone-releasing hormone (GHRH) neurons controlling the release of growth hormone. It is hypothesized that some of these effects occur in an indirect transsynaptic manner through the steroid regulation of GAGAergic inputs to these cells. Using GABA(A) receptor gamma(2) subunit knockout mice (gamma(2)(-/-)), which exhibit marked deficiencies in GABA(A) receptor functioning, we have examined here whether signaling through the GABA(A) receptor has any role in maintaining normal levels of somatostatin and GHRH mRNA expression in vivo. In situ hybridization experiments using (35)S-labeled oligonucleotide probes revealed that cellular levels of somatostatin mRNA in the periventricular nucleus were significantly (p < 0.01) reduced by 16% in newborn gamma(2)(-/-) mice compared with wild-type litter mates (gamma(2)(+/+)). Somatostatin mRNA expression in the striatum was not changed. Cellular levels of GHRH mRNA expression in the arcuate nucleus were significantly (p < 0.05) reduced by 30% in gamma(2)(-/-) compared with gamma(2)(+/+) mice. These results demonstrate that deletion of the gamma(2) subunit of the GABA(A) receptor reduces somatostatin and GHRH mRNA expression within the hypothalamopituitary axis and indicate that GABA exerts a tonic stimulatory influence upon both somatostatin and GHRH biosynthesis in vivo in the neonatal mouse.
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PMID:Hypothalamic somatostatin and growth hormone-releasing hormone mRNA expression depend upon GABA(A) receptor expression in the developing mouse. 1216 70

Patients and models of temporal lobe epilepsy have fewer inhibitory interneurons in the dentate gyrus than controls, but it is unclear whether granule cell inhibition is reduced. We report the loss of GABAergic inhibition of granule cells in the temporal dentate gyrus of pilocarpine-induced epileptic rats. In situ hybridization for GAD65 mRNA and immunocytochemistry for parvalbumin and somatostatin confirmed the loss of inhibitory interneurons. In epileptic rats, granule cells had prolonged EPSPs, and they discharged more action potentials than controls. Although the conductances of evoked IPSPs recorded in normal ACSF were not significantly reduced and paired-pulse responses showed enhanced inhibition of granule cells from epileptic rats, more direct measures of granule cell inhibition revealed significant deficiencies. In granule cells from epileptic rats, evoked monosynaptic IPSP conductances were <40% of controls, and the frequency of GABA(A) receptor-mediated spontaneous and miniature IPSCs (mIPSCs) was <50% of controls. Within 3-7 d after pilocarpine-induced status epilepticus, miniature IPSC frequency had decreased, and it remained low, without functional evidence of compensatory synaptogenesis by GABAergic axons in chronically epileptic rats. Both parvalbumin- and somatostatin-immunoreactive interneuron numbers and the frequency of both fast- and slow-rising GABA(A) receptor-mediated mIPSCs were reduced, suggesting that loss of inhibitory synaptic input to granule cells occurred at both proximal/somatic and distal/dendritic sites. Reduced granule cell inhibition in the temporal dentate gyrus preceded the onset of spontaneous recurrent seizures by days to weeks, so it may contribute, but is insufficient, to cause epilepsy.
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PMID:Reduced inhibition of dentate granule cells in a model of temporal lobe epilepsy. 1265 4


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