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Dive into the research topics where Erwin Sigel is active.

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Featured researches published by Erwin Sigel.


Neuron | 1990

The effect of subunit composition of rat brain GABAA receptors on channel function

Erwin Sigel; Roland Baur; Gerhard Trube; Hanms Möhler; Pari Malherbe

Different combinations of cloned rat brain subunit isoforms of the GABAA receptor channel were expressed in Xenopus oocytes. The voltage-clamp technique was then used to measure properties of the GABA-induced membrane currents and to study the effects of various modulators of the GABAA receptor channel (diazepam, DMCM, pentobarbital, and picrotoxin). This approach was used to obtain information on the minimal structural requirements for several functional properties of the ion channel. The combination alpha 5 beta 2 gamma 2 was identified as the minimal requirement reproducing consensus properties of the vertebrate GABAA receptor channel, including cooperativity of GABA-dependent channel gating with a Ka in the range of 10 microM, modulation by various drugs acting at the benzodiazepine binding site, picrotoxin sensitivity, and barbiturate effects.


Trends in Pharmacological Sciences | 1997

The benzodiazepine binding site of GABAA receptors

Erwin Sigel; Andreas Buhr

The GABAA receptor belongs, along with the nicotinic acetylcholine receptor, the glycine receptor and the 5-HT3 receptor, to a family of homologous transmitter-gated ion channels mediating fast synaptic transmission. Many classes of drug interact with the GABAA receptor, which is the major inhibitory ion channel in the mammalian brain. Among these drugs are the allosteric modulators acting at the benzodiazepine binding site. In this article, Erwin Sigel and Andreas Buhr discuss recent studies that have identified amino acid residues that are thought to form the binding pocket for these compounds. These residues are probably located at subunit interfaces of the protein pentamer and at least some of them are homologous to residues implicated in channel agonist binding. This implies pseudosymmetry of channel agonist and channel modulatory sites, which may be, as recent data indicate, a general principle realized in other pseudosymmetric protein complexes.


Journal of Biological Chemistry | 2012

Structure, function, and modulation of GABA(A) receptors.

Erwin Sigel; Michael E. Steinmann

The GABAA receptors are the major inhibitory neurotransmitter receptors in mammalian brain. Each isoform consists of five homologous or identical subunits surrounding a central chloride ion-selective channel gated by GABA. How many isoforms of the receptor exist is far from clear. GABAA receptors located in the postsynaptic membrane mediate neuronal inhibition that occurs in the millisecond time range; those located in the extrasynaptic membrane respond to ambient GABA and confer long-term inhibition. GABAA receptors are responsive to a wide variety of drugs, e.g. benzodiazepines, which are often used for their sedative/hypnotic and anxiolytic effects.


Biochemical Pharmacology | 2002

Anxiolytic Effect of Wogonin, a Benzodiazepine Receptor Ligand Isolated from Scutellaria Baicalensis Georgi

Kwok Min Hui; Michael S.Y. Huen; Hongyan Wang; Hui Zheng; Erwin Sigel; Roland Baur; Hong Ren; Zhi Wang Li; Jeffrey Tsz Fei Wong; Hong Xue

The search for novel anxiolytics devoid of undesirable side-effects typical of classical benzodiazepines (BDZs) has been intense, and flavonoids, as a relative new class of ligands, have been shown to possess anxiolytic effects in vivo. The present study evaluated the pharmacological properties of a naturally occurring monoflavonoid, 5,7-dihydroxy-8-methoxyflavone or wogonin. The affinity (K(i)) of wogonin for the benzodiazepine site (BZD-S) on the gamma-aminobutyric acid(A) (GABA(A)) receptor complex was 0.92 microM. Using electrophysiological techniques, we showed that wogonin enhanced the GABA-activated current in rat dorsal root ganglion neurons, and in Xenopus laevis oocytes expressing recombinant rat GABA(A) receptors, the enhancement was partially reversed by the co-application of a 1 microM concentration of the BZD-S antagonist anexate (Ro15-1788). Acute toxicity and behavioral effects were examined in mice. Acute lethal activity was low, with an LD(50) of 3.9 g/kg. Oral administration of wogonin (7.5 to 30 mg/kg) elicited an anxiolytic response that was similar to that elicited by diazepam in the elevated plus-maze; a dose-dependent increase in open arm entries and time spent in open arms was observed. More importantly, its anxiolytic effect was blocked by the co-administration of Ro15-1788. In the holeboard test, not only did wogonin-treated mice experience an increased number of head-dips but they also spent more time at it, showing no signs of sedation. Furthermore, wogonin did not cause myorelaxant effects in the horizontal wire test. Taken together, these data suggest that wogonin exerts its anxiolytic effect through positive allosteric modulation of the GABA(A) receptor complex via interaction at the BZD-S. Its anxiolytic effect was not accompanied by sedative and myorelaxant side-effects typical of BDZs.


British Journal of Pharmacology | 2004

The flavone hispidulin, a benzodiazepine receptor ligand with positive allosteric properties, traverses the blood–brain barrier and exhibits anticonvulsive effects

Dominique Kavvadias; Philipp Sand; Kuresh A. Youdim; M.Zeeshan Qaiser; Catherine Rice-Evans; Roland Baur; Erwin Sigel; Wolf-Dieter Rausch; Peter Riederer; Peter Schreier

The functional characterization of hispidulin (4′,5,7‐trihydroxy‐6‐methoxyflavone), a potent benzodiazepine (BZD) receptor ligand, was initiated to determine its potential as a modulator of central nervous system activity. After chemical synthesis, hispidulin was investigated at recombinant GABAA/BZD receptors expressed by Xenopus laevis oocytes. Concentrations of 50 nM and higher stimulated the GABA‐induced chloride currents at tested receptor subtypes (α1−3,5,6β2γ2S) indicating positive allosteric properties. Maximal stimulation at α1β2γ2S was observed with 10 μM hispidulin. In contrast to diazepam, hispidulin modulated the α6β2γ2S‐GABAA receptor subtype. When fed to seizure‐prone Mongolian gerbils (Meriones unguiculatus) in a model of epilepsy, hispidulin (10 mg kg−1 body weight (BW) per day) and diazepam (2 mg kg−1 BW per day) markedly reduced the number of animals suffering from seizures after 7 days of treatment (30 and 25% of animals in the respective treatment groups, vs 80% in the vehicle group). Permeability across the blood–brain barrier for the chemically synthesized, 14C‐labelled hispidulin was confirmed by a rat in situ perfusion model. With an uptake rate (Kin) of 1.14 ml min−1 g−1, measurements approached the values obtained with highly penetrating compounds such as diazepam. Experiments with Caco‐2 cells predict that orally administered hispidulin enters circulation in its intact form. At a concentration of 30 μM, the flavone crossed the monolayer without degradation as verified by the absence of glucuronidated metabolites.


The Journal of Membrane Biology | 1990

Use ofXenopus oocytes for the functional expression of plasma membrane proteins

Erwin Sigel

The phospholipid bilayer of the plasma membrane of the eucaryotic cell acts as a permeability barrier to many metabolic substrates and ions, whose transmembrane movement is catalyzed by selective membrane transport proteins. Control of cytosolic ion concentrations is achieved by the concerted action of numerous proteins working in the plasma membrane and the membranes of intracellular organelles: active pumps driven by ATP, carriers catalyzing coor countertransport and ion channels. A second important function of plasma membrane proteins is the reception of signals from the extracellular milieu, and the transmission of these signals either along the membrane, or across it, to the cytoplasmic side. The extracellular signals include such diverse entities as fast neurotransmitters, modulatory peptides, hormones, substrate-cell and cell-cell contacts. Many methods are now available for the study of mechanisms underlying membrane transport and signalling. Biochemical isolation and purification to homogeneity, reconstitution into artificial bilayer membranes, functional studies in these model systems, chemical modification, immunochemical and electrophysiological methods have helped to elucidate many features of membrane protein function. But, it should be emphasized here, that to date no protein catalyzed transmembrane transport mechanism is fully understood at the molecular level. The powerful tools recently developed by molecular biologists have raised new hopes for such an understanding. The availability of a quickly growing number of cDNA sequences coding for membrane transport


FEBS Letters | 1990

Functional expression and sites of gene transcription of a novel α subunit of the GABAA receptor in rat brain

Parichehr Malherbe; Erwin Sigel; Roland Baur; E. Persohn; Jg Richards; Hanns Möhler

Two α subunits of the gabaa receptor in rat brain have been identified by molecular cloning. The deduced polypeptide sequences share major characteristics with other chemically gated ion channel proteins. One polypeptide represents the rat homologue of the α3 subunit previously cloned from bovine brain [14], while the other polypeptide is a yet unknown subunit, termed α5. When coexpressed with the β1 subunit in Xenopus oocytes the receptors containing the α5 subunit revealed a higher sensitivity to GABA than receptors expressed from α1 + β1 subunits or α3 + β1 subunits (K a = 1 μM, 13 μM and 14 μM, respectively). The α5 subunit was expressed only in a few brain areas such as cerebral cortex, hippocampal formation and olfactory bulb granular layer as shown by in situ hybridization histochemistry. Since the mRNA of the α5 subunit was colocalized with the αl and α3 subunits only in cerebral cortex and in the hippocampal formation the α5 subunit may be part of distinct GABAA receptors in neuronal populations within the olfactory bulb.


FEBS Letters | 1993

Recombinant GABAA receptor function and ethanol.

Erwin Sigel; Roland Baur; Pari Malherbe

Different combinations of cloned subunits of the rat brain GABAA receptor were expressed in Xenopus oocytes. Possible effects of ethanol on the expressed GABA‐induced chloride current were determined. The consequence of replacing the γ2s subunit by the alternatively spliced variant γ2L was specifically tested on the responsiveness to ethanol. A significant stimulation of the GABA response was only observed at very high concentrations (> 60 mM) of ethanol. No differential response was observed between subunit combinations containing different γ2 subunit splice variants.


Neuropharmacology | 2002

The relative amount of cRNA coding for γ2 subunits affects stimulation by benzodiazepines in GABAA receptors expressed in Xenopus oocytes

A. J. Boileau; Roland Baur; L. M. Sharkey; Erwin Sigel; Cynthia Czajkowski

Benzodiazepine (BZD) potentiation of GABA-activated Cl(-)-current (I(GABA)) in recombinant GABA(A) receptors requires the presence of the gamma subunit. When alpha1, beta2 and gamma2S cRNA are expressed in a 1:1:1 ratio in Xenopus oocytes, BZD potentiation of I(GABA) is submaximal, variable and diminishes over time. Potentiation by BZDs is increased, more reproducible and is stabilized over time by increasing the relative amount of cRNA coding for the gamma2S subunit. In addition, GABA EC(50) values for alpha1beta2gamma2 (1:1:1) receptors are intermediate to values measured for alpha1beta2 (1:1) and alpha1beta2gamma2 (1:1:10) receptors. We conclude that co-expression of equal ratios of alpha1, beta2 and gamma2 subunits in Xenopus oocytes produces a mixed population of alpha1beta2 and alpha1beta2gamma2 receptors. Therefore, for accurate measurements of BZD potentiation it is necessary to inject a higher ratio of gamma2 subunit cRNA relative to alpha1 and beta2 cRNA. This results in a purer population of alpha1beta2gamma2 receptors.


FEBS Letters | 1991

Activation of protein kinase C results in down-modulation of different recombinant GABAA-channels.

Erwin Sigel; Roland Baur; Pari Malherbe

Different combinations of cloned rat brain subunits of the GABAA receptor were expressed in Xenopus oocytes. The effect of the phorbol ester PMA, an activator of protein kinase C, on the expressed GABA‐gated ion current was determined. Ion currents were diminished by β‐PMA, but not by the control substance α‐PMA, irrespective of the subunit combination studied. The mechanism of current decrease was investigated in more detail for the subunit combination α5β2γ2. The reversal potential of the current remained unaffected, while the maximal current amplitude was decreased and the apparent K a for GABA‐dependent channel gating was shifted to higher concentrations.

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Werner Sieghart

Medical University of Vienna

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Pascal Mäser

Swiss Tropical and Public Health Institute

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Margot Ernst

Medical University of Vienna

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