Pharmacological modulation of GABAA receptors

Knoflach, Frédéric; Bertrand, Daniel

doi:10.1016/j.coph.2021.04.003

Cited by 16 publications

(12 citation statements)

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“…To assess the modulation of native GABA A Rs by gelsemine, we carried out electrophysiological experiments on mouse cultured S1; Ralvenius et al, 2015;Knoflach and Bertrand, 2021). In line with these data, the GABA-evoked currents obtained from these neurons were sensitive to diazepam (64.6 ± 10.9%, n = 7, 2 μM diazepam.…”

Section: Gelsemine Modulation Of Native Gaba a Rs Expressed In Cortic...mentioning

confidence: 70%

“…To determine whether gelsemine may behave as a positive allosteric modulator of GABA A Rs, we examined the effects of gelsemine on the BDZ-sensitive GABA A Rs configurations expressed on mammalian synapses ( Fritschy, 2015 ; Ralvenius et al, 2015 ; Knoflach and Bertrand, 2021 ) using whole-cell patch clamp recordings. We first determined the GABA sensitivity of recombinant α1β2γ2, α2β3γ2, α3β3γ2 and α5β2γ2 expressed on HEK 293 cells ( Table 1 ; Figure 1A ).…”

Section: Resultsmentioning

confidence: 99%

“…Consequently, we evaluated the effects of gelsemine on GABA A Rs composed of α1(H101R)β2γ2 and of α1β2 subunits. The point-mutated α1GABA A R subunit contains a histidine-to-arginine mutation at the position 101 which disrupts the BDZ binding site, generating GABA A Rs insensitive to diazepam but normally sensitive to the agonist GABA ( Benson et al, 1998 ; Ralvenius et al, 2015 ; Knoflach and Bertrand, 2021 ). We select the α1β2γ2 subtype to assess the relevance of the BDZ binding site because is the most widely expressed GABA A R subtype in the brain ( Fritschy, 2015 ).…”

Section: Resultsmentioning

confidence: 99%

“…Despite its potential relevance as a gelsemine target, potential direct actions of the alkaloid on GABA A Rs and on GABAergic synapses have been minimally studied. Since GABA A Rs are the main biological targets of benzodiazepines (BDZs), the mainstay group of drugs used to treat anxiety and sleep disorders, and of other clinically relevant drugs, a potentiation of GABA A Rs by gelsemine has been considered as a potential mechanism of action ( Ghit et al, 2021 ; Knoflach and Bertrand, 2021 ). In addition, the analgesic effects of classical BDZs ( Ralvenius et al, 2015 ) suggest a contribution of gelsemine to pain control through GABA A Rs.…”

Section: Introductionmentioning

confidence: 99%

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Modulation of GABAA receptors and of GABAergic synapses by the natural alkaloid gelsemine

Marileo

Gavilán²,

Martín³

et al. 2023

Front. Mol. Neurosci.

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The Gelsemium elegans plant preparations have shown beneficial activity against common diseases, including chronic pain and anxiety. Nevertheless, their clinical uses are limited by their toxicity. Gelsemine, one of the most abundant alkaloids in the Gelsemium plants, have replicated these therapeutic and toxic actions in experimental behavioral models. However, the molecular targets underlying these biological effects remain unclear. The behavioral activity profile of gelsemine suggests the involvement of GABAA receptors (GABAARs), which are the main biological targets of benzodiazepines (BDZs), a group of drugs with anxiolytic, hypnotic, and analgesic properties. Here, we aim to define the modulation of GABAARs by gelsemine, with a special focus on the subtypes involved in the BDZ actions. The gelsemine actions were determined by electrophysiological recordings of recombinant GABAARs expressed in HEK293 cells, and of native receptors in cortical neurons. Gelsemine inhibited the agonist-evoked currents of recombinant and native receptors. The functional inhibition was not associated with the BDZ binding site. We determined in addition that gelsemine diminished the frequency of GABAergic synaptic events, likely through a presynaptic modulation. Our findings establish gelsemine as a negative modulator of GABAARs and of GABAergic synaptic function. These pharmacological features discard direct anxiolytic or analgesic actions of gelsemine through GABAARs but support a role of GABAARs on the alkaloid induced toxicity. On the other hand, the presynaptic effects of the alkaloid provide an additional mechanism to explain their beneficial effects. Collectively, our results contribute novel information to improve understanding of gelsemine actions in the mammalian nervous system.

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Section: Gelsemine Modulation Of Native Gaba a Rs Expressed In Cortic...mentioning

confidence: 70%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Modulation of GABAA receptors and of GABAergic synapses by the natural alkaloid gelsemine

Marileo

Gavilán²,

Martín³

et al. 2023

Front. Mol. Neurosci.

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“…Данный класс мембранных рецепторов, осуществляющих торможение в нейронах, относится к семейству гетеропентомерных лиганд-зависимых хлорных каналов (pentameric ligand-gated ion channels, pLGICs) [5,6]. Взаимодействие агониста с рецептором, приводящее к открытию селективного анионного канала на поверхности возбудимой мембраны, приводит к увеличению потока Cl -, обуславливающего гиперполяризацию нейрона [7]. Данная активация трансмембранного анионного тока через ГАМК А рецепторы позволяет в классическом подходе к DOI: 10.19163/2307-9266-2022-10-5-404-415 Том 10, Выпуск 5, 2022 нейрофизиологическим процессам рассматривать ГАМК в качестве основного тормозного нейромедиатора в центральной нервной системе (ЦНС) [8].…”

Section: Introductionunclassified

Molecular Mechanisms Defining Application of Glycine and Zinc Combinationin Correction of Stress and Anxiety Main Manifestations

Shishkova

Nartsissov

Titova

et al. 2022

Farm. farmakol. (Pâtigorsk)

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The aim of the work was to carry out a systematic analysis of the molecular mechanisms that determine the possibility of a combined use of amino acid glycine and zinc compounds for the treatment of patients with manifestations of stress and anxiety.Materials and methods. Information retrieval (Scopus, PubMed) and library (eLibrary) databases were used as research tools. In some cases, the ResearchGate application was applied for a semantic search. The analysis and generalization of references was carried out on the research topic, covering the period from 2000 to the present time.Results. It has been shown that amino acid glycine, along with gamma-aminobutyric acid (GABA), is a key neurotransmitter that regulates physiological inhibition processes in the central nervous system (CNS) by increasing transmembrane conductance in specific pentameric ligand-gated ion channels. The introduction of zinc ions can potentiate the opening of these receptors by increasing their affinity for glycine, resulting in an inhibitory processes increase in CNS neurons. The replenishment of the glycine and zinc combined deficiency is an important element in the correction of a post-stress dysfunction of the central nervous system. A balanced intake of zinc and glycine is essential for most people who experience daily effects of multiple stresses and anxiety. This combination is especially useful for the people experiencing a state of chronic psycho-emotional stress and maladaptation, including those who have a difficulty in falling asleep.Conclusion. A balanced maintenance of the zinc and glycine concentration in the body of a healthy person leads to the development of a stable anti-anxiety effect, which is accompanied by the normalization of the sleep-wake rhythm, which makes it possible to have a good rest without any loss of working efficiency after waking up.

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Detection of Flunitrazepam in Biological Fluids and Beverages:A Review

Chen,

Huang,

Qiu

et al. 2023

ChemistrySelect

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Flunitrazepam, a very potent benzodiazepine with sedative, hypnotic and amnesic effects, is commonly used to treat severe insomnia and as an anesthetic. Due to these characteristics, when flunitrazepam is sneaked into alcohol or drinks, it is often highly associated with violent behavior and drug rape cases. Therefore, it is also known as a “date rape drug”, and the detection of flunitrazepam and its metabolites is of great interest in forensic medicine and pharmacotoxicology. This paper describes the mechanism of action and drug metabolism process of flunitrazepam, reviews the different methods for detecting flunitrazepam published over the years, summarizes the detection limits of each method and compares their advantages and disadvantages. We hope to provide some inspiration for future research in this field.

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Pharmacological modulation of GABAA receptors

Cited by 16 publications

References 56 publications

Modulation of GABAA receptors and of GABAergic synapses by the natural alkaloid gelsemine

Modulation of GABAA receptors and of GABAergic synapses by the natural alkaloid gelsemine

Molecular Mechanisms Defining Application of Glycine and Zinc Combinationin Correction of Stress and Anxiety Main Manifestations

Detection of Flunitrazepam in Biological Fluids and Beverages:A Review

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