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)

To elucidate the mechanism by which carbamazepine lowers somatostatin concentration in cerebrospinal fluid of humans, the effect of carbamazepine on secretion of this peptide was studied in rat cerebral cell cultures. Concentrations of carbamazepine within the therapeutic range (4 x 10(-5) M) inhibited spontaneous release of somatostatin and blocked secretory responses to the epileptogen, picrotoxin, and to the cyclic cAMP stimulator forskolin. One of the proposed mechanisms of carbamazepine action is that it binds to adenosine receptors, but in this study, aminophylline, an adenosine antagonist, in a concentration as high as 2.4 x 10(-4) M, did not reverse carbamazepine effects. Carbamazepine suppression of picrotoxin, however, was overcome by exposure to veratridine, a sodium channel-active compound. This finding supports the hypothesis that carbamazepine acts by binding to sodium channels. Phenytoin, another anticonvulsant with many similar properties, also blocked picrotoxin-induced somatostatin release at a concentration of 10(-4) M, and its effects were also reversed by veratridine at a concentration of 10(-5) M. These findings clarify the mechanism by which carbamazepine and phenytoin act in epilepsy and trigeminal neuralgia.
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PMID:Carbamazepine and phenytoin inhibit somatostatin release from dispersed cerebral cells in culture. 168 80

The cellular mechanisms by which the hypothalamic peptide somatostatin (SRIF) inhibits Ca+(+) influx were investigated in the pituitary cell line AtT-20. Cytosolic Ca+(+) levels were measured using the fluorescent probe Quin 2. Calcium influx was stimulated by the Ca+(+) channel agonist Bay K 8644. Bay K 8644 increased Ca+(+) influx in a concentration-dependent manner and the stimulation of Ca+(+) influx was blocked by the Ca+(+) channel antagonists nifedipine and nitrendipine. SRIF analogs also blocked Bay K 8644-stimulated Ca+(+) influx. The rank order of potency of the analogs (SRIF-28 greater than D-Trp8-SRIF greater than SRIF) suggests that the effects of SRIF are mediated by SRIF-28 preferring receptors. Pretreatment of AtT-20 cells with pertussis toxin abolished SRIF's inhibition of Bay K 8644-evoked Ca+(+) influx suggesting that G proteins mediate the inhibitory effects of SRIF on Ca+(+) influx. The K+ channel antagonists tetraethylammonium, 4-aminopyridine and CsCl all stimulated Ca+(+) influx into AtT-20 cells. These agents did not alter Bay K 8644-evoked Ca+(+) influx or did they affect the ability of SRIF to inhibit Ca+(+) influx. Tetrodotoxin, the sodium channel blocker which inhibits action potential generation in AtT-20 cells, lowered basal Ca+(+) levels in AtT-20 cells but did not modify SRIF's inhibition of Bay K 8644-stimulated Ca+(+) influx. These findings suggest that SRIF receptors, linked directly to Ca+(+) channels via G proteins, may mediate SRIF's inhibition of Ca+(+) influx.
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PMID:Cellular mechanisms of somatostatin inhibition of calcium influx in the anterior pituitary cell line AtT-20. 169 31

The influence of membrane depolarization on somatostatin secretion and protein synthesis by fetal and neonatal cerebrocortical neurons was studied. Cortical cells obtained by mechanical dispersion were maintained as monolayer cultures for 8 days. The ability of fetal cerebrocortical and hypothalamic cells to release immunoreactive somatostatin (IR-SRIF) was confirmed. Total protein synthesis was determined by the incorporation of [3H]phenylalanine into trichloroacetic acid-precipitable proteins. To study the effect of acute depolarization on protein synthesis, cells were incubated for 30 min with [3H]phenylalanine or [3H]leucine and the depolarizing agent. In fetal cerebrocortical cells, potassium (30 and 56 mM) decreased protein synthesis and RNA levels and increased IR-SRIF release. Depolarization by veratridine, a sodium channel activator, induced a similar effect. The effect of veratridine on IR-SRIF and protein synthesis was reversed by tetrodotoxin, a sodium channel blocker, or verapamil, a calcium channel blocker. These findings suggest that protein synthesis by cerebrocortical cells is decreased in fetal brain cells by membrane depolarization and is dependent on Na+ and Ca2+ entry into cells. In postnatal (day 7) cerebrocortical cells, depolarization induced by high potassium concentrations led to a concomitant increase in protein synthesis, RNA content, and somatostatin release. These findings indicate that depolarization of the cellular membrane is coupled to an increase in protein synthesis in neonatal, but not in fetal, dispersed brain cells.
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PMID:Divergent effects of acute depolarization on somatostatin release and protein synthesis in cultured fetal and neonatal rat brain cells. 246 35

The influence of membrane depolarization on somatostatin release from cerebral cortical neurons was examined. Fetal rat telencephalic cells, obtained by mechanoenzymatic dispersal, were maintained as organotypic monolayer cultures for 12 days before experimental studies. The immunoreactive somatostatin (IRS) released into the medium during a treatment epoch was compared to the amount released from the same cells during an immediately preceding control period. Potassium (60 mM) induced an increase in IRS secretion which was dependent on extracellular calcium concentration and could be prevented by the addition of the calcium channel blockers, cobalt or verapamil. Depolarization by veratridine, a sodium ionophore, also stimulated IRS release. The effect of veratridine was reversed by simultaneous exposure of the cells to either tetrodotoxin, a sodium channel blocker, or verapamil, a calcium channel blocker. These findings indicate that IRS release by cerebral cortical cells is stimulated by membrane depolarization and is dependent on both Na+ and Ca++ entry into the cells.
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PMID:Sodium- and calcium-dependent somatostatin release from dissociated cerebral cortical cells in culture. 612 71

Extracellular levels of somatostatin in the rat striatum were studied using in vivo microdialysis and radioimmunoassay. In vitro studies were performed using three different dialysis membranes at various flow rates and temperatures to assess the optimal recovery of somatostatin. The best results were obtained when a cellulose fibre membrane was utilized at 37 degrees C with a flow rate of 0.5 microliters/min. For the in vivo studies, transcerebral cellulose probes were implanted in the striatum of chloryl hydrate-anaesthetized rats. Basal levels of somatostatin were detected in the striatum of the freely moving animals and found to be 5-15 fmol. Stimulation with 100 mM KCl increased the recovered somatostatin by 138% (P < 0.05). A second stimulation following a 3-h interval increased the somatostatin levels by approximately 60%. The addition of veratridine (100 microM) in the perfusion medium increased the somatostatin levels recovered from the striatum by 85% (P < 0.01). Following a 3-h interval, a second stimulation by veratridine also increased somatostatin levels (43%). The increases observed after the second depolarizing stimulus (KCl and veratridine) were not found to be significantly different from basal levels. Both EGTA and the sodium channel blocker tetrodotoxin attenuated the effect of KCl and veratridine, respectively. However, neither EGTA nor tetrodotoxin had an effect on the basal levels of somatostatin recovered. These results indicate that (i) the somatostatin measured is neuronally released in the striatum and (ii) microdialysis is a useful tool for examining the regulation of somatostatin release in the brain.
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PMID:Neuronal release of somatostatin in the rat striatum: an in vivo microdialysis study. 810 42

Haploinsufficiency of the voltage-gated sodium channel NaV1.1 causes Dravet syndrome, an intractable developmental epilepsy syndrome with seizure onset in the first year of life. Specific heterozygous deletion of NaV1.1 in forebrain GABAergic-inhibitory neurons is sufficient to cause all the manifestations of Dravet syndrome in mice, but the physiological roles of specific subtypes of GABAergic interneurons in the cerebral cortex in this disease are unknown. Voltage-clamp studies of dissociated interneurons from cerebral cortex did not detect a significant effect of the Dravet syndrome mutation on sodium currents in cell bodies. However, current-clamp recordings of intact interneurons in layer V of neocortical slices from mice with haploinsufficiency in the gene encoding the NaV1.1 sodium channel, Scn1a, revealed substantial reduction of excitability in fast-spiking, parvalbumin-expressing interneurons and somatostatin-expressing interneurons. The threshold and rheobase for action potential generation were increased, the frequency of action potentials within trains was decreased, and action-potential firing within trains failed more frequently. Furthermore, the deficit in excitability of somatostatin-expressing interneurons caused significant reduction in frequency-dependent disynaptic inhibition between neighboring layer V pyramidal neurons mediated by somatostatin-expressing Martinotti cells, which would lead to substantial disinhibition of the output of cortical circuits. In contrast to these deficits in interneurons, pyramidal cells showed no differences in excitability. These results reveal that the two major subtypes of interneurons in layer V of the neocortex, parvalbumin-expressing and somatostatin-expressing, both have impaired excitability, resulting in disinhibition of the cortical network. These major functional deficits are likely to contribute synergistically to the pathophysiology of Dravet syndrome.
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PMID:Impaired excitability of somatostatin- and parvalbumin-expressing cortical interneurons in a mouse model of Dravet syndrome. 2502 83

Severe myoclonic epilepsy of infancy (SMEI) is associated with loss of function of the SCN1A gene encoding the NaV1.1 sodium channel isoform. Previous studies in Scn1a(-/+) mice during the pre-epileptic period reported selective reduction in interneuron excitability and proposed this as the main pathological mechanism underlying SMEI. Yet, the functional consequences of this interneuronal dysfunction at the circuit level in vivo are unknown. Here, we investigated whether Scn1a(-/+) mice showed alterations in cortical network function. We found that various forms of spontaneous network activity were similar in Scn1a(-/+) during the pre-epileptic period compared with wild-type (WT) in vivo. Importantly, in brain slices from Scn1a(-/+) mice, the excitability of parvalbumin (PV) and somatostatin (SST) interneurons was reduced, epileptiform activity propagated more rapidly, and complex synaptic changes were observed. However, in vivo, optogenetic reduction of firing in PV or SST cells in WT mice modified ongoing network activities, and juxtasomal recordings from identified PV and SST interneurons showed unaffected interneuronal firing during spontaneous cortical dynamics in Scn1a(-/+) compared with WT. These results demonstrate that interneuronal hypoexcitability is not observed in Scn1a(-/+) mice during spontaneous activities in vivo and suggest that additional mechanisms may contribute to homeostatic rearrangements and the pathogenesis of SMEI.
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PMID:Unaltered Network Activity and Interneuronal Firing During Spontaneous Cortical Dynamics In Vivo in a Mouse Model of Severe Myoclonic Epilepsy of Infancy. 2681 75