The Experts below are selected from a list of 42756 Experts worldwide ranked by ideXlab platform
M. P. Mccarthy - One of the best experts on this subject based on the ideXlab platform.
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Effects of the androgenic/anabolic steroid stanozolol on GABAA Receptor function: GABA-stimulated 36Cl- influx and [35S] TBPS binding.
Journal of Pharmacology and Experimental Therapeutics, 1996Co-Authors: A. E. T. Masonis, M. P. MccarthyAbstract:We have recently demonstrated that androgenic/anabolic steroids modulate in vitro ligand binding to the benzodiazepine binding site(s) associated with the gamma-aminobutyric acidA (GABAA) Receptor complex (Masonis and McCarthy, 1995). One androgenic/anabolic steroid in particular, stanozolol, appears to stabilize the GABAA Receptor in a moderate-affinity state for benzodiazepine binding. In the present study, we demonstrate the effects of stanozolol on the functional responsiveness of the GABAA Receptor. After pre-incubation with stanozolol, we observed a decrease in the Emax and EC50 values for GABA-stimulated 36Cl- influx into cortical synaptoneurosomes. Moreover, in the presence of stanozolol, flunitrazepam-enhanced GABA-stimulated 36Cl- influx was lost, and the GABAA Receptor was stabilized in a functional state that was resistant to further desensitization by agonist. Stanozolol does not appear to reduce GABA-stimulated 36Cl- influx by acting as a channel blocker at the well-characterized channel blocker binding site, as illustrated by the GABA-sensitive biphasic effects of stanozolol on [35S] t-butylbicyclophosphorothionate binding. These results demonstrate a novel, nongenomic mechanism for androgenic/anabolic steroidal modulation of CNS function.
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effects of the androgenic anabolic steroid stanozolol on GABAA Receptor function gaba stimulated 36cl influx and 35s tbps binding
Journal of Pharmacology and Experimental Therapeutics, 1996Co-Authors: A. E. T. Masonis, M. P. MccarthyAbstract:We have recently demonstrated that androgenic/anabolic steroids modulate in vitro ligand binding to the benzodiazepine binding site(s) associated with the gamma-aminobutyric acidA (GABAA) Receptor complex (Masonis and McCarthy, 1995). One androgenic/anabolic steroid in particular, stanozolol, appears to stabilize the GABAA Receptor in a moderate-affinity state for benzodiazepine binding. In the present study, we demonstrate the effects of stanozolol on the functional responsiveness of the GABAA Receptor. After pre-incubation with stanozolol, we observed a decrease in the Emax and EC50 values for GABA-stimulated 36Cl- influx into cortical synaptoneurosomes. Moreover, in the presence of stanozolol, flunitrazepam-enhanced GABA-stimulated 36Cl- influx was lost, and the GABAA Receptor was stabilized in a functional state that was resistant to further desensitization by agonist. Stanozolol does not appear to reduce GABA-stimulated 36Cl- influx by acting as a channel blocker at the well-characterized channel blocker binding site, as illustrated by the GABA-sensitive biphasic effects of stanozolol on [35S] t-butylbicyclophosphorothionate binding. These results demonstrate a novel, nongenomic mechanism for androgenic/anabolic steroidal modulation of CNS function.
Robert L. Macdonald - One of the best experts on this subject based on the ideXlab platform.
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a structural look at GABAA Receptor mutations linked to epilepsy syndromes
Brain Research, 2019Co-Authors: Ciria C Hernandez, Robert L. MacdonaldAbstract:Understanding the genetic variation in GABAA Receptor subunit genes (GABRs), GABRA1-6, GABRB1-3, GABRG1-3 and GABRD, in individuals affected by epilepsy may improve the diagnosis and treatment of epilepsy syndromes through identification of disease-associated variants. However, the lack of functional analysis and validation of many novel and previously reported familial and de novo mutations have made it challenging to address meaningful gene associations with epilepsy syndromes. GABAA Receptors belong to the Cys-loop Receptor family. Even though GABAA Receptor mutant residues are widespread among different GABRs, their frequent occurrence in important structural domains that share common functional features suggests associations between structure and function.
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GABAA Receptor epilepsy mutations
Biochemical pharmacology, 2004Co-Authors: Robert L. Macdonald, Martin J. Gallagher, Hua-jun Feng, Jing-qiong KangAbstract:Idiopathic generalized epilepsy (IGE) syndromes are diseases that are characterized by absence, myoclonic, and/or primary generalized tonic-clonic seizures in the absence of structural brain abnormalities. Although it was long hypothesized that IGE had a genetic basis, only recently have causative genes been identified. Here we review mutations in the GABAA Receptor α1, γ2, and δ subunits that have been associated with different IGE syndromes. These mutations affect GABAA Receptor gating, expression, and/or trafficking of the Receptor to the cell surface, all pathophysiological mechanisms that result in neuronal disinhibition and thus predispose affected patients to seizures.
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Functional GABAA Receptor heterogeneity of acutely dissociated hippocampal CA1 pyramidal cells.
Journal of Neurophysiology, 1999Co-Authors: Elizabeth I. Tietz, Jaideep Kapur, Robert L. MacdonaldAbstract:Functional GABAA Receptor heterogeneity of acutely dissociated hippocampal CA1 pyramidal cells. CA1 pyramidal cells were voltage clamped, and GABA was applied to individual cells with a modified U-...
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Native and Recombinant GABAA Receptor Channels
Cellular Physiology and Biochemistry, 1993Co-Authors: Robert L. Macdonald, Timothy AngelottiAbstract:Biochemical, pharmacological and electrophysiological techniques have been used to characterize GABAA Receptor (GABAR) channels in mammalian brain and have demonstrated the existence of a p
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Regulation of GABAA Receptor channels by anticonvulsant and convulsant drugs and by phosphorylation.
Epilepsy research. Supplement, 1992Co-Authors: Robert L. Macdonald, R E Twyman, Ryan-jastrow T, Timothy AngelottiAbstract:The GABAA Receptor channel is a highly regulated Receptor. The function of the Receptor may be modified by drugs which alter the rates of binding of GABA, modify the gating of the channel or block the channel. It is also likely that phosphorylation of the Receptor subunits modifies the biophysical properties, stability or assembly of the Receptor. While GABAergic inhibition plays a major role in the regulation of neuronal excitability, a role for altered GABAergic inhibition in the pathogenesis of epilepsy remains to be proven. The demonstration that GABAA Receptors are composed of multiple subunits and that the properties and pharmacology of GABAA Receptors are different for different subunit combinations suggests that GABAA Receptor heterogeneity may be of importance in determining the properties of GABAergic inhibition in different regions of the nervous system. While it is clear that GABAA Receptor heterogeneity is present in the nervous system, a role for Receptor heterogeneity in the pathogenesis of epilepsy remains uncertain. GABAA Receptor heterogeneity may have implications for the treatment of epilepsy. It is quite possible that drugs which regulate GABAergic function may have variable efficacy in different regions of the nervous system due to expression of Receptors with subunits that have different sensitivity to allosteric regulators. Furthermore, it is likely that there are developmental changes in the stoichiometry or subunit composition of GABAA Receptors rendering the developing nervous system more or less sensitive to the effects of GABAergic anticonvulsant drugs. In addition to the heterogeneous expression of GABAA Receptors, other issues concerning the regulation of GABAergic function are of potential importance. The regulatory events that control the expression of specific Receptor subtypes and levels of GABA Receptors are unknown. The post-translational events that regulate GABAA Receptor function are uncertain. It is possible that post-translational regulation of GABAA Receptors by phosphorylation may contribute to altered GABAA Receptor function in epilepsy. To understand the role of GABAA Receptor heterogeneity in the pathogenesis of epilepsy will require the combination of biophysical and molecular biological techniques. It will be important to determine not only whether the properties of GABAA Receptors have been altered in a specific form of epilepsy, but also whether gene expression has been altered.
A. E. T. Masonis - One of the best experts on this subject based on the ideXlab platform.
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Effects of the androgenic/anabolic steroid stanozolol on GABAA Receptor function: GABA-stimulated 36Cl- influx and [35S] TBPS binding.
Journal of Pharmacology and Experimental Therapeutics, 1996Co-Authors: A. E. T. Masonis, M. P. MccarthyAbstract:We have recently demonstrated that androgenic/anabolic steroids modulate in vitro ligand binding to the benzodiazepine binding site(s) associated with the gamma-aminobutyric acidA (GABAA) Receptor complex (Masonis and McCarthy, 1995). One androgenic/anabolic steroid in particular, stanozolol, appears to stabilize the GABAA Receptor in a moderate-affinity state for benzodiazepine binding. In the present study, we demonstrate the effects of stanozolol on the functional responsiveness of the GABAA Receptor. After pre-incubation with stanozolol, we observed a decrease in the Emax and EC50 values for GABA-stimulated 36Cl- influx into cortical synaptoneurosomes. Moreover, in the presence of stanozolol, flunitrazepam-enhanced GABA-stimulated 36Cl- influx was lost, and the GABAA Receptor was stabilized in a functional state that was resistant to further desensitization by agonist. Stanozolol does not appear to reduce GABA-stimulated 36Cl- influx by acting as a channel blocker at the well-characterized channel blocker binding site, as illustrated by the GABA-sensitive biphasic effects of stanozolol on [35S] t-butylbicyclophosphorothionate binding. These results demonstrate a novel, nongenomic mechanism for androgenic/anabolic steroidal modulation of CNS function.
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effects of the androgenic anabolic steroid stanozolol on GABAA Receptor function gaba stimulated 36cl influx and 35s tbps binding
Journal of Pharmacology and Experimental Therapeutics, 1996Co-Authors: A. E. T. Masonis, M. P. MccarthyAbstract:We have recently demonstrated that androgenic/anabolic steroids modulate in vitro ligand binding to the benzodiazepine binding site(s) associated with the gamma-aminobutyric acidA (GABAA) Receptor complex (Masonis and McCarthy, 1995). One androgenic/anabolic steroid in particular, stanozolol, appears to stabilize the GABAA Receptor in a moderate-affinity state for benzodiazepine binding. In the present study, we demonstrate the effects of stanozolol on the functional responsiveness of the GABAA Receptor. After pre-incubation with stanozolol, we observed a decrease in the Emax and EC50 values for GABA-stimulated 36Cl- influx into cortical synaptoneurosomes. Moreover, in the presence of stanozolol, flunitrazepam-enhanced GABA-stimulated 36Cl- influx was lost, and the GABAA Receptor was stabilized in a functional state that was resistant to further desensitization by agonist. Stanozolol does not appear to reduce GABA-stimulated 36Cl- influx by acting as a channel blocker at the well-characterized channel blocker binding site, as illustrated by the GABA-sensitive biphasic effects of stanozolol on [35S] t-butylbicyclophosphorothionate binding. These results demonstrate a novel, nongenomic mechanism for androgenic/anabolic steroidal modulation of CNS function.
A R Aricescu - One of the best experts on this subject based on the ideXlab platform.
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A structural perspective on GABAA Receptor pharmacology.
Current opinion in structural biology, 2019Co-Authors: Suzanne Scott, A R AricescuAbstract:GABAA Receptors are pentameric ligand-gated chloride channels of crucial importance for the vertebrate nervous system physiology. They typically modulate the fast inhibitory neurotransmission, and represent the target Receptors for major classes of drugs used in the clinic, such as benzodiazepines and general anesthetics. Recent technological progress in structural biology, in particular single-particle cryo-electron microscopy, has led to fundamental advances in understanding the detailed organization and signalling mechanisms of major GABAA Receptor subtypes. This effort culminated with the high-resolution structural analysis of an intact, full-length human heteropentameric Receptor, α1β3γ2, in a lipid bilayer and in complex with small molecule ligands including the commonly used benzodiazepines diazepam (Valium) and alprazolam (Xanax). These structures reveal multiple aspects of Receptor activation and provide a path for rational design of subunit-specific GABAA Receptor modulators.
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Structural basis for GABAA Receptor potentiation by neurosteroids.
Nature Structural & Molecular Biology, 2017Co-Authors: Paul S. Miller, Suzanne Scott, S. Masiulis, Luigi De Colibus, Els Pardon, Jan Steyaert, A R AricescuAbstract:Crystal structures and functional assays of a chimeric GABAA Receptor in apo and pregnanolone-bound states reveal how neurosteroid binding alters Receptor conformation to modulate channel opening.
Timothy Angelotti - One of the best experts on this subject based on the ideXlab platform.
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Native and Recombinant GABAA Receptor Channels
Cellular Physiology and Biochemistry, 1993Co-Authors: Robert L. Macdonald, Timothy AngelottiAbstract:Biochemical, pharmacological and electrophysiological techniques have been used to characterize GABAA Receptor (GABAR) channels in mammalian brain and have demonstrated the existence of a p
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Regulation of GABAA Receptor channels by anticonvulsant and convulsant drugs and by phosphorylation.
Epilepsy research. Supplement, 1992Co-Authors: Robert L. Macdonald, R E Twyman, Ryan-jastrow T, Timothy AngelottiAbstract:The GABAA Receptor channel is a highly regulated Receptor. The function of the Receptor may be modified by drugs which alter the rates of binding of GABA, modify the gating of the channel or block the channel. It is also likely that phosphorylation of the Receptor subunits modifies the biophysical properties, stability or assembly of the Receptor. While GABAergic inhibition plays a major role in the regulation of neuronal excitability, a role for altered GABAergic inhibition in the pathogenesis of epilepsy remains to be proven. The demonstration that GABAA Receptors are composed of multiple subunits and that the properties and pharmacology of GABAA Receptors are different for different subunit combinations suggests that GABAA Receptor heterogeneity may be of importance in determining the properties of GABAergic inhibition in different regions of the nervous system. While it is clear that GABAA Receptor heterogeneity is present in the nervous system, a role for Receptor heterogeneity in the pathogenesis of epilepsy remains uncertain. GABAA Receptor heterogeneity may have implications for the treatment of epilepsy. It is quite possible that drugs which regulate GABAergic function may have variable efficacy in different regions of the nervous system due to expression of Receptors with subunits that have different sensitivity to allosteric regulators. Furthermore, it is likely that there are developmental changes in the stoichiometry or subunit composition of GABAA Receptors rendering the developing nervous system more or less sensitive to the effects of GABAergic anticonvulsant drugs. In addition to the heterogeneous expression of GABAA Receptors, other issues concerning the regulation of GABAergic function are of potential importance. The regulatory events that control the expression of specific Receptor subtypes and levels of GABA Receptors are unknown. The post-translational events that regulate GABAA Receptor function are uncertain. It is possible that post-translational regulation of GABAA Receptors by phosphorylation may contribute to altered GABAA Receptor function in epilepsy. To understand the role of GABAA Receptor heterogeneity in the pathogenesis of epilepsy will require the combination of biophysical and molecular biological techniques. It will be important to determine not only whether the properties of GABAA Receptors have been altered in a specific form of epilepsy, but also whether gene expression has been altered.