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GABAA receptors mediate inhibitory transmission in the adult mammalian brain and are modulated by many clinically used drugs such as benzodiazepines. It has pre‑ viously been demonstrated that benzodiazepines affect binding and gating transitions. However, the mechanism of their modulation is still not fully understood. In our present study we address this problem by examining modulation of spontaneous...
BACKGROUND AND AIMS: The GABAA receptor is the main mediator responsible for inhibitory transmission in the brain. In our previous work (Szczot et al. 2014), we demonstrated for α1β2γ2 receptors that “classical” channel gating (opening/closing and desensitization) is preceded by a preactivation step, which is most likely initiated at the agonist-binding site. Here, we investigated the role of β2E155...
BACKGROUND AND AIMS: GABAA receptors (GABAAR) mediate the main component of ionotropic inhibitory transmission in adult mammalian brain. These receptors are heteropentamers and are strongly diversified throughout the CNS but the most frequent subunit composition is alpha1-beta2-gamma2. It has been reported that alpha1-gamma2 receptors can be potently expressed in recombinant GABAAR model (Verdoorn...
GABAARs are crucial for neuronal inhibition. Using patch-clamp technique with ultrafast perfusion we found that mutations of hydrophobic residue at GABA-binding site affected not only binding affinity but also kinetics of macroscopic desensitization. Nonstationary variance analysis indicated that α1F64C mutation reduces maximum open probability. To obtain further information about the role of α1F64...
In spite of broad knowledge of GABAAR pharmacokinetics, molecular mechanisms of conformation transitions remain elusive. Intriguingly, GABA binding site is distant from the channel gate (ca. 5 nm). In this study we searched for residues at GABA binding site involved in conveying binding energy to the channel gate of α1β2γ2 GABAARs. Mutation at α1F64 decreased the receptor affinity (shifted dose-response...
GABAA receptor (GABAAR) is a pentamer, formed by 2α, 2β and γ subunit. GABA binding site is localized at the interface between α and β subunits. Our aim was to characterize how mutation localized at the binding pocket (α1F64) influences agonist binding and conformational transitions between bound receptor states (gating). We used patchclamp technique with ultrafast perfusion system and HEK 293 cells...
Despite broad knowledge on GABAA receptors (GABAARs) structure, the mechanism of ligand induced conformational transitions remains poorly understood. To address this issue we have examined the activity of a recombinant α1/β1/γ2 GABAAR with point mutation introduced at the ligand binding site. Currents were elicited by ultrafast GABA applications and measured using patch-clamp technique. We show that...
Monoterpenoid α-thujone is a compound found in absinthe, alcoholic beverage commonly abused (often by famous artists) in late XIX and early XX century. It has been long speculated that α-thujone is responsible for some adverse effects of this liquor including seizures. It has been investigated that the effect of α-thujone is related to its action on GABAA receptors but a precise pharmacological analysis...