Pre- and post-synaptic mechanisms regulating the clustering of type A γ-aminobutyric acid receptors (GABAA receptors)

2003 ◽  
Vol 31 (4) ◽  
pp. 889-892 ◽  
Author(s):  
J.-M. Fritschy ◽  
C. Schweizer ◽  
I. Brünig ◽  
B. Lüscher
Keyword(s):  
Neuronal Activity ◽  
Protein Complex ◽  
Gabaa Receptors ◽  
Synapse Formation ◽  
Type A ◽  
Aminobutyric Acid ◽  
Proper Function ◽  
Gabaergic Synapses ◽  
Synaptic Mechanisms

Postsynaptic clustering of GABAA (type A γ-aminobutyric acid) receptors is essential to ensure proper function of GABAergic synapses. This process is initiated during synapse formation and is maintained throughout life. The tubulin-associated protein gephyrin is required for clustering of GABAA receptors, but its specific role in this process is not understood. A second protein associated selectively with GABAA receptors at postsynaptic sites is dystrophin. It is present in a subset of GABAergic synapses along with several partners, forming the dystrophin-associated protein complex. In this review, we discuss recent advances in the role of neuronal activity and trans-synaptic signaling for the clustering of gephyrin and dystrophin during synaptogenesis and on the role of these proteins for plasticity and maintenance of mature synapses.

scholarly journals Differential Regulation of the Postsynaptic Clustering of γ-Aminobutyric Acid Type A (GABAA) Receptors by Collybistin Isoforms

2011 ◽  
Vol 286 (25) ◽  
pp. 22456-22468 ◽  
Author(s):  
Tzu-Ting Chiou ◽  
Bevan Bonhomme ◽  
Hongbing Jin ◽  
Celia P. Miralles ◽  
Haiyan Xiao ◽  
...  
Keyword(s):  
Gabaa Receptors ◽  
Type A ◽  
Differential Regulation ◽  
Aminobutyric Acid ◽  
Acid Type

Classic Benzodiazepines Modulate the Open–Close Equilibrium in α1β2γ2Lγ-Aminobutyric Acid Type A Receptors

2005 ◽  
Vol 102 (4) ◽  
pp. 783-792 ◽  
Author(s):  
Dirk Rüsch ◽  
Stuart A. Forman
Keyword(s):  
Gabaa Receptors ◽  
Sulfonic Acid ◽  
Site Occupancy ◽  
Type A ◽  
Aminobutyric Acid ◽  
Clinical Effects ◽  
Gamma Aminobutyric Acid ◽  
Wild Type ◽  
Acid Type ◽  
Benzodiazepine Site

Background Classic benzodiazepine agonists induce their clinical effects by binding to a site on gamma-aminobutyric acid type A (GABAA) receptors and enhancing receptor activity. There are conflicting data regarding whether the benzodiazepine site is allosterically coupled to gamma-aminobutyric acid binding versus the channel open-close (gating) equilibrium. The authors tested the hypothesis that benzodiazepine site ligands modulate alpha1beta2gamma2L GABAA receptor gating both in the absence of orthosteric agonists and when the orthosteric sites are occupied. Methods GABAA receptors were recombinantly expressed in Xenopus oocytes and studied using two-microelectrode voltage clamp electrophysiology. To test gating effects in the absence of orthosteric agonist, the authors used spontaneously active GABAA receptors containing a leucine-to-threonine mutation at residue 264 on the alpha1 subunit. To examine effects on gating when orthosteric sites were fully occupied, they activated wild-type receptors with high concentrations of a partial agonist, piperidine-4-sulfonic acid. Results In the absence of orthosteric agonists, the channel activity of alpha1L264Tbeta2gamma2L receptors was increased by diazepam and midazolam and reduced by the inverse benzodiazepine agonist FG7142. Flumazenil displayed very weak agonism and blocked midazolam from further activating mutant channels. In wild-type receptors activated with saturating concentrations of piperidine-4-sulfonic acid, midazolam increased maximal efficacy. Conclusions Independent of orthosteric site occupancy, classic benzodiazepines modulate the gating equilibrium in alpha1beta2gamma2L GABAA receptors and are therefore allosteric coagonists. A Monod-Wyman-Changeux coagonist gating model quantitatively predicts these effects, suggesting that benzodiazepines minimally alter orthosteric ligand binding.

scholarly journals A Cysteine Substitution Probes β3H267 Interactions with Propofol and Other Potent Anesthetics in α1β3γ2L γ-Aminobutyric Acid Type A Receptors

2016 ◽  
Vol 124 (1) ◽  
pp. 89-100 ◽  
Author(s):  
Alex T. Stern ◽  
Stuart A. Forman
Keyword(s):  
Gabaa Receptors ◽  
Barbituric Acid ◽  
Type A ◽  
Homology Model ◽  
Aminobutyric Acid ◽  
Mammalian Brain ◽  
Cysteine Substitution ◽  
Acid Type ◽  
Study Results ◽  
Contact Residues

Abstract Background Anesthetic contact residues in γ-aminobutyric acid type A (GABAA) receptors have been identified using photolabels, including two propofol derivatives. O-propofol diazirine labels H267 in β3 and α1β3 receptors, whereas m-azi-propofol labels other residues in intersubunit clefts of α1β3. Neither label has been studied in αβγ receptors, the most common isoform in mammalian brain. In αβγ receptors, other anesthetic derivatives photolabel m-azi-propofol-labeled residues, but not βH267. The authors’ structural homology model of α1β3γ2L receptors suggests that β3H267 may abut some of these sites. Methods Substituted cysteine modification–protection was used to test β3H267C interactions with four potent anesthetics: propofol, etomidate, alphaxalone, and R-5-allyl-1-methyl-5-(m-trifluoromethyl-diazirinylphenyl) barbituric acid (mTFD-MPAB). The authors expressed α1β3γ2L or α1β3H267Cγ2L GABAA receptors in Xenopus oocytes. The authors used voltage clamp electrophysiology to assess receptor sensitivity to γ-aminobutyric acid (GABA) and anesthetics and to compare p-chloromercuribenzenesulfonate modification rates with GABA versus GABA plus anesthetics. Results Enhancement of low GABA (eliciting 5% of maximum) responses by equihypnotic concentrations of all four anesthetics was similar in α1β3γ2L and α1β3H267Cγ2L receptors (n > 3). Direct activation of α1β3H267Cγ2L receptors, but not α1β3γ2L, by mTFD-MPAB and propofol was significantly greater than the other anesthetics. Modification of β3H267C by p-chloromercuribenzenesulfonate (n > 4) was rapid and accelerated by GABA. Only mTFD-MPAB slowed β3H267C modification (approximately twofold; P = 0.011). Conclusions β3H267 in α1β3γ2L GABAA receptors contacts mTFD-MPAB, but not propofol. The study results suggest that β3H267 is near the periphery of one or both transmembrane intersubunit (α+/β− and γ+/β−) pockets where both mTFD-MPAB and propofol bind.

scholarly journals Role of spinal GABAA receptors in pudendal inhibition of nociceptive and nonnociceptive bladder reflexes in cats

2014 ◽  
Vol 306 (7) ◽  
pp. F781-F789 ◽  
Author(s):  
Zhiying Xiao ◽  
Jeremy Reese ◽  
Zeyad Schwen ◽  
Bing Shen ◽  
Jicheng Wang ◽  
...  
Keyword(s):  
Gabaa Receptors ◽  
Bladder Capacity ◽  
Aminobutyric Acid ◽  
Saline Control ◽  
Receptor Subtype ◽  
High Dose ◽  
Multiple Threshold ◽  
Bladder Activity ◽  
Subtype A

Picrotoxin, an antagonist for γ-aminobutyric acid receptor subtype A (GABAA), was used to investigate the role of GABAA receptors in nociceptive and nonnociceptive reflex bladder activities and pudendal inhibition of these activities in cats under α-chloralose anesthesia. Acetic acid (AA; 0.25%) was used to irritate the bladder and induce nociceptive bladder overactivity, while saline was used to distend the bladder and induce nonnociceptive bladder activity. To modulate the bladder reflex, pudendal nerve stimulation (PNS) was applied at multiple threshold (T) intensities for inducing anal sphincter twitching. AA irritation significantly ( P < 0.01) reduced bladder capacity to 34.3 ± 7.1% of the saline control capacity, while PNS at 2T and 4T significantly ( P < 0.01) increased AA bladder capacity to 84.0 ± 7.8 and 93.2 ± 15.0%, respectively, of the saline control. Picrotoxin (0.4 mg it) did not change AA bladder capacity but completely removed PNS inhibition of AA-induced bladder overactivity. Picrotoxin (iv) only increased AA bladder capacity at a high dose (0.3 mg/kg) but significantly ( P < 0.05) reduced 2T PNS inhibition at low doses (0.01–0.1 mg/kg). During saline cystometry, PNS significantly ( P < 0.01) increased bladder capacity to 147.0 ± 7.6% at 2T and 172.7 ± 8.9% at 4T of control capacity, and picrotoxin (0.4 mg it or 0.03–0.3 mg/kg iv) also significantly ( P < 0.05) increased bladder capacity. However, picrotoxin treatment did not alter PNS inhibition during saline infusion. These results indicate that spinal GABAA receptors have different roles in controlling nociceptive and nonnociceptive reflex bladder activities and in PNS inhibition of these activities.

Structure–Function Evaluation of Imidazopyridine Derivatives Selective for δ-Subunit-Containing γ-Aminobutyric Acid Type A (GABAA) Receptors

2018 ◽  
Vol 61 (5) ◽  
pp. 1951-1968 ◽  
Author(s):  
Kirsten Yakoub ◽  
Sascha Jung ◽  
Christian Sattler ◽  
Helen Damerow ◽  
Judith Weber ◽  
...  
Keyword(s):  
Structure Function ◽  
Gabaa Receptors ◽  
Type A ◽  
Aminobutyric Acid ◽  
Function Evaluation ◽  
Acid Type ◽  
Imidazopyridine Derivatives

scholarly journals Etomidate and Etomidate Analog Binding and Positive Modulation of γ-Aminobutyric Acid Type A Receptors

2018 ◽  
Vol 129 (5) ◽  
pp. 959-969 ◽  
Author(s):  
Megan McGrath ◽  
Zhiyi Yu ◽  
Selwyn S. Jayakar ◽  
Celena Ma ◽  
Mansi Tolia ◽  
...  
Keyword(s):  
Steric Hindrance ◽  
Gabaa Receptors ◽  
Binding Sites ◽  
Phenyl Ring ◽  
Type A ◽  
Binding Pocket ◽  
Aminobutyric Acid ◽  
Substituent Group ◽  
Acid Type ◽  
Site Selective

Abstract Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New Background Naphthalene-etomidate, an etomidate analog containing a bulky phenyl ring substituent group, possesses very low γ-aminobutyric acid type A (GABAA) receptor efficacy and acts as an anesthetic-selective competitive antagonist. Using etomidate analogs containing phenyl ring substituents groups that range in volume, we tested the hypothesis that this unusual pharmacology is caused by steric hindrance that reduces binding to the receptor’s open state. Methods The positive modulatory potencies and efficacies of etomidate and phenyl ring–substituted etomidate analogs were electrophysiology defined in oocyte-expressed α1β3γ2L GABAA receptors. Their binding affinities to the GABAA receptor’s two classes of transmembrane anesthetic binding sites were assessed from their abilities to inhibit receptor labeling by the site-selective photolabels 3[H]azi-etomidate and tritiated R-5-allyl-1-methyl-5-(m-trifluoromethyl-diazirynylphenyl) barbituric acid. Results The positive modulatory activities of etomidate and phenyl ring–substituted etomidate analogs progressively decreased with substituent group volume, reflecting significant decreases in both potency (P = 0.005) and efficacy (P &lt; 0.0001). Affinity for the GABAA receptor’s two β+ − α– anesthetic binding sites similarly decreased with substituent group volume (P = 0.003), whereas affinity for the receptor’s α+ – β–/γ+ – β– sites did not (P = 0.804). Introduction of the N265M mutation, which is located at the β+ − α– binding sites and renders GABAA receptors etomidate-insensitive, completely abolished positive modulation by naphthalene-etomidate. Conclusions Steric hindrance selectively reduces phenyl ring–substituted etomidate analog binding affinity to the two β+ − α– anesthetic binding sites on the GABAA receptor’s open state, suggesting that the binding pocket where etomidate’s phenyl ring lies becomes smaller as the receptor isomerizes from closed to open.

scholarly journals Correct Laminar Positioning in the Neocortex Influences Proper Dendritic and Synaptic Development

2018 ◽  
Vol 28 (8) ◽  
pp. 2976-2990 ◽  
Author(s):  
Fanny Sandrine Martineau ◽  
Surajit Sahu ◽  
Vanessa Plantier ◽  
Emmanuelle Buhler ◽  
Fabienne Schaller ◽  
...  
Keyword(s):  
Neuronal Migration ◽  
Cortical Neurons ◽  
Neuronal Development ◽  
Synapse Formation ◽  
Functional Organization ◽  
Functional Integration ◽  
Proper Function ◽  
Cortical Circuits ◽  
Gabaergic Synapses ◽  
Dendrite Morphogenesis

Abstract The neocortex is a 6-layered laminated structure with a precise anatomical and functional organization ensuring proper function. Laminar positioning of cortical neurons, as determined by termination of neuronal migration, is a key determinant of their ability to assemble into functional circuits. However, the exact contribution of laminar placement to dendrite morphogenesis and synapse formation remains unclear. Here we manipulated the laminar position of cortical neurons by knocking down doublecortin (Dcx), a crucial effector of migration, and show that misplaced neurons fail to properly form dendrites, spines, and functional glutamatergic and GABAergic synapses. We further show that knocking down Dcx in properly positioned neurons induces similar but milder defects, suggesting that the laminar misplacement is the primary cause of altered neuronal development. Thus, the specific laminar environment of their fated layers is crucial for the maturation of cortical neurons, and influences their functional integration into developing cortical circuits.

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