Somatostatin Inhibits Excitatory Transmission at Rat Hippocampal Synapses via Presynaptic Receptors

Boehm, Stefan; Betz, Heinrich

doi:10.1523/jneurosci.17-11-04066.1997

Cited by 149 publications

(135 citation statements)

References 62 publications

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“…We showed that SST reduced excitatory postsynaptic currents evoked by stimulating Schaeffer collaterals (Tallent and Siggins, 1997). This effect is likely due to presynaptic inhibition of glutamate release by SST (Boehm and Betz, 1997). Thus SST has synergistic pre-and postsynaptic actions that reduce CA1 pyramidal cell excitability.…”

Section: Sst Inhibition Of Epileptiform Activity In Hippocampal Slicesmentioning

confidence: 72%

Somatostatin: An endogenous antiepileptic

Tallent

Qiu

2008

Molecular and Cellular Endocrinology

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The neuropeptide somatostatin is highly expressed in brain regions associated with seizures. In hippocampus, SST expression and release is regulated by seizures, and SST-containing neurons within the hilus of the dentate gyrus are sensitive to seizure-induced death. In vivo and in vitro studies suggest that the loss of SST function in the dentate could contribute to epileptogenesis and seizure susceptibility. SST also has inhibitory actions in the CA1 and CA3 hippocampus, indicating this peptide is an important homeostatic regulator throughout the hippocampus. In vivo studies show SST has robust antiepileptic properties, with the major site of action being hippocampus. In rodents, somatostatin receptor subtype 2 (SST 2 ) and SST 4 appear to mediate the majority of the antiepileptic actions of SST, with SST 2 predominate in rat and SST 4 in mouse. Thus SST receptors may be appropriate targets for new antiepileptic drugs, although validation in human tissue is lacking.

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Section: Sst Inhibition Of Epileptiform Activity In Hippocampal Slicesmentioning

confidence: 72%

Somatostatin: An endogenous antiepileptic

Tallent

Qiu

2008

Molecular and Cellular Endocrinology

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“…Hippocampal neurons were prepared from neonatal rats as in Ref. 8. Glial cells were depleted by a 16-h incubation in the presence of 1 M cytarabine (AraC).…”

Section: Methodsmentioning

confidence: 99%

Two Discontinuous Segments in the Carboxyl Terminus Are Required for Membrane Targeting of the Rat γ-Aminobutyric Acid Transporter-1 (GAT1)

Farhan

Korkhov

Paulitschke

et al. 2004

Journal of Biological Chemistry

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Like all members of the Na؉ /Cl ؊ -dependent neurotransmitter transporter family, the rat ␥-aminobutyric acid transporter-1 (GAT1) is sorted and targeted to specialized domains of the cell surface. Here we identify two discontinuous signals in the carboxyl terminus of GAT1 that cooperate to drive surface expression. This conclusion is based on the following observations. Upon deletion of the last 37 amino acids, the resulting GAT1-⌬37 remained trapped in the endoplasmic reticulum. The presence of 10 additional residues (GAT1-⌬27) sufficed to support the interaction with the coat protein complex II component Sec24D; surface expression of GAT1-⌬27 reached 50% of the wild type level. Additional extensions up to the position ؊3 (GAT1-⌬3) did not further enhance surface expression. Thus the last three amino acids (AYI) comprise a second distal signal. The sequence AYI is reminiscent of a type II PDZ-binding motif; accordingly substituting Glu for Ile abrogated the effect of this motif. Neither the AYI motif nor the last 10 residues rescued the protein from intracellular retention when grafted onto GAT1-⌬37 and GAT1-⌬32; the AYI motif was dispensable for targeting of GAT1 to the growth cone of differentiating PC12 cells. We therefore conclude that the two segments act in a hierarchical manner such that the proximal motif ( 569 VMI 571 ) supports endoplasmic reticulum export of the protein and the distal AYI motif places GAT1 under the control of the exocyst.Neurotransmission at synaptic junctions in the central nervous system is terminated by reuptake of the neurotransmitter into the synaptic ends (1). This is achieved by neurotransmitter transporters. GABA 1 is the major inhibitory neurotransmitter in the brain. There are three GABA transporters, referred to as GAT1, GAT2, and GAT3, which all belong to the Na ϩ /Cl Ϫ -dependent neurotransmitter transporter family. Members of this family share several features including a characteristic topology, i.e. intracellular amino and the carboxyl termini and a hydrophobic core composed of 12 transmembrane-spanning segments that are presumed to be predominantly ␣-helical. In the brain, GAT1 is the most widely distributed isoform. The transporter is of obvious therapeutic relevance: increases in synaptic GABA reduces excitability and prevents excessive neuronal firing. This action provides a rationale for the use of tiagabine in the treatment of epilepsy (2). In neurons, transporters must reach the presynaptic specialization. Thus, their biosynthetic pathway must also comprise mechanisms that afford the sorting and targeting to the axonal compartment and/or specific retention at perisynaptic sites (3). In addition, they undergo quality control in the endoplasmic reticulum (4) and posttranslational modification in the Golgi stacks. We recently demonstrated that neurotransmitter transporters such as GAT1 and the serotonin transporter form constitutive oligomers (5). If oligomerization of GAT1 is disrupted, the transporter is no longer expressed at the cell surface but is retained ...

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“…From these data, as well as a number of animal experiments on the effect of seizure activity of somatostatin, it was concluded that somatostatin has neuroprotective function and anti-epileptic action [39]. Indeed, somatostatin inhibits spontaneous and evoked epileptiform bursting in vitro [40] while reducing glutamate release in the hippocampus [41]. Somatostatin, injected intracerebroventricularly [42] or overexpressed in the hippocampus using viral tools [43] decreased the severity of seizures in vivo.…”

Section: Somatostatinmentioning

confidence: 98%

Receptors of Peptides as Therapeutic Targets in Epilepsy Research

Dobolyi¹,

Kékesi²,

Juhász³

et al. 2014

CMC

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Neuropeptides are signaling molecules participating in the modulation of synaptic transmission. Neuropeptides are stored in dense core synaptic vesicles, the release of which requires profound excitation. Only in the extracellular space, neuropeptides act on G-protein coupled receptors to exert a relatively slow action both pre-and postsynaptically. Consequently, neuropeptide modulators are ideal candidates to influence epileptic tissue overexcited during seizures. Indeed, a number of neuropeptides have been implicated in epilepsy and many of them are considered to have endogenous neuroprotective actions. Neuropeptides, present in the hippocampus, the most frequent focus of seizures in temporal lobe epilepsy, received the largest attention as potential anti-epileptic substances. Hippocampal neuropeptides, somatostatin, neuropeptide Y, galanin, dynorphin, enkephalin, substance P, cholecystokinin, vasoactive intestinal polypeptide, and some neuropeptides, which are also hormones such as ghrelin, angiotensins, corticotropin-releasing hormone, adrenocorticotropin, thyrotropin-releasing hormone, oxytocin and vasopressin involved in epilepsy are discussed in the review article. Oral application of neuropeptides as drugs is typically not efficient because of low bioavailability: rapid degradation and insufficient penetration through the blood-brain barrier. Recent progress in the development of non-peptide agonists and antagonists of neuropeptide receptors as well as gene therapeutic approaches leading to the local production of neuropeptides within the central nervous system will also be discussed.

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Somatostatin Inhibits Excitatory Transmission at Rat Hippocampal Synapses via Presynaptic Receptors

Cited by 149 publications

References 62 publications

Somatostatin: An endogenous antiepileptic

Somatostatin: An endogenous antiepileptic

Two Discontinuous Segments in the Carboxyl Terminus Are Required for Membrane Targeting of the Rat γ-Aminobutyric Acid Transporter-1 (GAT1)

Receptors of Peptides as Therapeutic Targets in Epilepsy Research

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