scholarly journals Shisa7 is a GABAA receptor auxiliary subunit controlling benzodiazepine actions

Science ◽  
2019 ◽  
Vol 366 (6462) ◽  
pp. 246-250 ◽  
Author(s):  
Wenyan Han ◽  
Jun Li ◽  
Kenneth A. Pelkey ◽  
Saurabh Pandey ◽  
Xiumin Chen ◽  
...  
Keyword(s):  
Transmembrane Protein ◽  
Clinical Importance ◽  
Aminobutyric Acid ◽  
Inhibitory Synapses ◽  
Channel Pore ◽  
Auxiliary Subunit ◽  
Deactivation Kinetics ◽  
Acid Type ◽  
Genetic Deletion ◽  
The Brain

The function and pharmacology of γ-aminobutyric acid type A receptors (GABAARs) are of great physiological and clinical importance and have long been thought to be determined by the channel pore–forming subunits. We discovered that Shisa7, a single-passing transmembrane protein, localizes at GABAergic inhibitory synapses and interacts with GABAARs. Shisa7 controls receptor abundance at synapses and speeds up the channel deactivation kinetics. Shisa7 also potently enhances the action of diazepam, a classic benzodiazepine, on GABAARs. Genetic deletion of Shisa7 selectively impairs GABAergic transmission and diminishes the effects of diazepam in mice. Our data indicate that Shisa7 regulates GABAAR trafficking, function, and pharmacology and reveal a previously unknown molecular interaction that modulates benzodiazepine action in the brain.

The role of GABAA receptor biogenesis, structure and function in epilepsy

2006 ◽  
Vol 34 (5) ◽  
pp. 863-867 ◽  
Author(s):  
S. Mizielinska ◽  
S. Greenwood ◽  
C.N. Connolly
Keyword(s):  
Gabaa Receptor ◽  
Structure And Function ◽  
Inhibitory Synapses ◽  
Normal Brain ◽  
Synaptic Targeting ◽  
Acid Type ◽  
Normal Brain Function ◽  
And Function ◽  
The Brain

Maintaining the correct balance in neuronal activation is of paramount importance to normal brain function. Imbalances due to changes in excitation or inhibition can lead to a variety of disorders ranging from the clinically extreme (e.g. epilepsy) to the more subtle (e.g. anxiety). In the brain, the most common inhibitory synapses are regulated by GABAA (γ-aminobutyric acid type A) receptors, a role commensurate with their importance as therapeutic targets. Remarkably, we still know relatively little about GABAA receptor biogenesis. Receptors are constructed as pentameric ion channels, with α and β subunits being the minimal requirement, and the incorporation of a γ subunit being necessary for benzodiazepine modulation and synaptic targeting. Insights have been provided by the discovery of several specific assembly signals within different GABAA receptor subunits. Moreover, a number of recent studies on GABAA receptor mutations associated with epilepsy have further enhanced our understanding of GABAA receptor biogenesis, structure and function.

scholarly journals Neurosteroids and GABAergic signaling in health and disease

2013 ◽  
Vol 4 (1) ◽  
pp. 29-42 ◽  
Author(s):  
Georgina MacKenzie ◽  
Jamie Maguire
Keyword(s):  
Sexual Behaviors ◽  
Neuronal Excitability ◽  
De Novo ◽  
Aminobutyric Acid ◽  
Acid Type ◽  
Direct Binding ◽  
Health And Disease ◽  
Local Metabolism ◽  
The Brain ◽  
Large Charge

AbstractEndogenous neurosteroids such as allopregnanolone, allotetrahydrodeoxycorticosterone, and androstanediol are synthesized either de novo in the brain from cholesterol or are generated from the local metabolism of peripherally derived progesterone or corticosterone. Fluctuations in neurosteroid concentrations are important in the regulation of a number of physiological responses including anxiety and stress, reproductive, and sexual behaviors. These effects are mediated in part by the direct binding of neurosteroids to γ-aminobutyric acid type-A receptors (GABAARs), resulting in the potentiation of GABAAR-mediated currents. Extrasynaptic GABAARs containing the δ subunit, which contribute to the tonic conductance, are particularly sensitive to low nanomolar concentrations of neurosteroids and are likely their preferential target. Considering the large charge transfer generated by these persistently open channels, even subtle changes in neurosteroid concentrations can have a major impact on neuronal excitability. Consequently, aberrant levels of neurosteroids have been implicated in numerous disorders, including, but not limited to, anxiety, neurodegenerative diseases, alcohol abuse, epilepsy, and depression. Here we review the modulation of GABAAR by neurosteroids and the consequences for health and disease.

Influence of GABAAReceptor γ2Splice Variants on Receptor Kinetics and Isoflurane Modulation

2004 ◽  
Vol 101 (4) ◽  
pp. 924-936 ◽  
Author(s):  
Claudia Benkwitz ◽  
Matthew I. Banks ◽  
Robert A. Pearce
Keyword(s):  
Charge Transfer ◽  
Gabaa Receptors ◽  
Current Amplitude ◽  
Aminobutyric Acid ◽  
Gamma Aminobutyric Acid ◽  
General Anesthetics ◽  
Net Charge ◽  
Peak Current ◽  
Deactivation Kinetics ◽  
The Brain

Background Gamma-aminobutyric acid type A (GABAA) receptors, the major inhibitory receptors in the brain, are important targets of many drugs, including general anesthetics. These compounds exert multiple effects on GABAA receptors, including direct activation, prolongation of deactivation kinetics, and reduction of inhibitory postsynaptic current amplitudes. However, the degree to which these actions occur differs for different agents and synapses, possibly because of subunit-specific effects on postsynaptic receptors. In contrast to benzodiazepines and intravenous anesthetics, there is little information available about the subunit dependency of actions of volatile anesthetics. Therefore, the authors studied in detail the effects of isoflurane on recombinant GABAA receptors composed of several different subunit combinations. Methods Human embryonic kidney 293 cells were transiently transfected with rat complementary DNAs of alpha1beta2, alpha1beta2gamma2L, alpha1beta2gamma2S, alpha5beta3, or alpha5beta3gamma2S subunits. Using rapid application and whole cell patch clamp techniques, cells were exposed to 10- and 2,000-ms pulses of gamma-aminobutyric acid (1 mm) in the presence or absence of isoflurane (0.25, 0.5, 1.0 mm). Anesthetic effects on decay kinetics, peak amplitude, net charge transfer and rise time were measured. Statistical significance was assessed using the Student t test or one-way analysis of variance followed by the Tukey post hoc test. Results Under control conditions, incorporation of a gamma2 subunit conferred faster deactivation kinetics and reduced desensitization. Isoflurane slowed deactivation, enhanced desensitization, and reduced peak current amplitude in alphabeta receptors. Coexpression with a gamma2 subunit caused these effects of isoflurane to be substantially reduced or abolished. Although the two gamma2 splice variants imparted qualitatively similar macroscopic kinetic properties, there were significant quantitative differences between effects of isoflurane on deactivation and peak current amplitude in gamma2S- versus gamma2L-containing receptors. The net charge transfer resulting from brief pulses of gamma-aminobutyric acid was decreased by isoflurane in alphabeta but increased in alphabetagamma receptors. Conclusions The results indicate that subunit composition does substantially influence modulation of GABAA receptors by isoflurane. Specifically, the presence of a gamma2 subunit and the identity of its splice variant are important factors in determining physiologic and pharmacologic properties. These results may have functional implications in understanding how anesthetic effects on specific types of GABAA receptors in the brain contribute to changes in brain function and behavior.

Neonatal Exposure to a Combination of N -Methyl-d-aspartate and γ-Aminobutyric Acid Type A Receptor Anesthetic Agents Potentiates Apoptotic Neurodegeneration and Persistent Behavioral Deficits

2007 ◽  
Vol 107 (3) ◽  
pp. 427-436 ◽  
Author(s):  
Anders Fredriksson ◽  
Emma Pontén ◽  
Torsten Gordh ◽  
Per Eriksson
Keyword(s):  
Type A ◽  
Brain Cell ◽  
Aminobutyric Acid ◽  
Growth Spurt ◽  
High Dose ◽  
Gamma Aminobutyric Acid ◽  
Behavioral Deficits ◽  
Anesthetic Agents ◽  
Acid Type ◽  
The Brain

Background During the brain growth spurt, the brain develops and modifies rapidly. In rodents this period is neonatal, spanning the first weeks of life, whereas in humans it begins during the third trimester and continues 2 yr. This study examined whether different anesthetic agents, alone and in combination, administered to neonate mice, can trigger apoptosis and whether behavioral deficits occur later in adulthood. Methods Ten-day-old mice were injected subcutaneously with ketamine (25 mg/kg), thiopental (5 mg/kg or 25 mg/kg), propofol (10 mg/kg or 60 mg/kg), a combination of ketamine (25 mg/kg) and thiopental (5 mg/kg), a combination of ketamine (25 mg/kg) and propofol (10 mg/kg), or control (saline). Fluoro-Jade staining revealed neurodegeneration 24 h after treatment. The behavioral tests--spontaneous behavior, radial arm maze, and elevated plus maze (before and after anxiolytic)--were conducted on mice aged 55-70 days. Results Coadministration of ketamine plus propofol or ketamine plus thiopental or a high dose of propofol alone significantly triggered apoptosis. Mice exposed to a combination of anesthetic agents or ketamine alone displayed disrupted spontaneous activity and learning. The anxiolytic action of diazepam was less effective when given to adult mice that were neonatally exposed to propofol. Conclusion This study shows that both a gamma-aminobutyric acid type A agonist (thiopental or propofol) and an N-methyl-D-aspartate antagonist (ketamine) during a critical stage of brain development potentiated neonatal brain cell death and resulted in functional deficits in adulthood. The use of thiopental, propofol, and ketamine individually elicited no or only minor changes.

scholarly journals The role of GABAAR phosphorylation in the construction of inhibitory synapses and the efficacy of neuronal inhibition

2009 ◽  
Vol 37 (6) ◽  
pp. 1355-1358 ◽  
Author(s):  
Mansi Vithlani ◽  
Stephen J. Moss
Keyword(s):  
Adaptor Protein ◽  
Inhibitory Synapses ◽  
Receptor Subtypes ◽  
Neuronal Structure ◽  
Neuronal Inhibition ◽  
Acid Type ◽  
Selective Ligand ◽  
Direct Binding ◽  
Clathrin Adaptor ◽  
The Brain

GABAARs [GABA (γ-aminobutyric acid) type-A receptors] are heteropentameric chloride-selective ligand-gated ion channels that mediate fast inhibition in the brain and are key therapeutic targets for benzodiazepines, barbiturates, neurosteroids and general anaesthetics. In the brain, most of the benzodiazepine-sensitive synaptic receptor subtypes are assembled from α1-3, β1-3 and γ2 subunits. Although it is evident that the pharmacological manipulation of GABAAR function can have profound effects on behaviour, the endogenous mechanisms that neurons use to promote sustained changes in the efficacy of neuronal inhibition remain to be documented. It is increasingly clear that GABAARs undergo significant rates of constitutive endocytosis and regulate recycling processes that can determine the efficacy of synaptic inhibition. Their endocytosis is regulated via the direct binding of specific endocytosis motifs within the intracellular domains of receptor β1-3and γ2 subunits to the clathrin adaptor protein AP2 (adaptor protein 2). These binding motifs contain major sites of both serine and tyrosine phosphorylation within GABAARs. Their phosphorylation can have dramatic effects on binding to AP2. In the present review, we evaluate the role that these phospho-dependent interactions play in regulating the construction of inhibitory synapses, efficacy of neuronal inhibition and neuronal structure.

scholarly journals Brain neurosteroids are natural anxiolytics targeting α2 subunit γ-aminobutyric acid type-A receptors

2018 ◽  
Author(s):  
Elizabeth J Durkin ◽  
Laurenz Muessig ◽  
Tanja Herlt ◽  
Michael J Lumb ◽  
Ryan Patel ◽  
...  
Keyword(s):  
Stress Hormones ◽  
Type A ◽  
Aminobutyric Acid ◽  
Anxiety And Depression ◽  
Neurotransmitter Receptor ◽  
Inhibitory Neurotransmitter ◽  
Naturally Occurring ◽  
Acid Type ◽  
The Brain

AbstractNeurosteroids are naturally-occurring molecules in the brain that modulate neurotransmission. They are physiologically important since disrupting their biosynthesis precipitates neurological disorders, such as anxiety and depression. The endogenous neurosteroids, allopregnanolone and tetrahydro-deoxycorticosterone are derived from sex and stress hormones respectively, and exhibit therapeutically-useful anxiolytic, analgesic, sedative, anticonvulsant and antidepressant properties. Their main target is the γ-aminobutyric acid type-A inhibitory neurotransmitter receptor (GABAAR), whose activation they potentiate. However, whether specific GABAAR isoforms and neural circuits differentially mediate endogenous neurosteroid effects is unknown. By creating a knock-in mouse that removes neurosteroid potentiation from α2-GABAAR subunits, we reveal that this isoform is a key target for neurosteroid modulation of phasic and tonic inhibition, and is essential for the anxiolytic role of endogenous neurosteroids, but not for their anti-depressant or analgesic properties. Overall, α2-GABAAR targeting neurosteroids may act as selective anxiolytics for the treatment of anxiety disorders, providing new therapeutic opportunities for drug development.

Sign in / Sign up

Export Citation Format

Share Document