Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Receptors, GABA-A”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 19 recordsLinked to original sources
PubMed1992

Invertebrate GABA and glutamate receptors: molecular biology reveals predictable structures but some unusual pharmacologies.

Determination of the sequences of invertebrate gamma-aminobutyric acid (GABA)-gated and glutamate-gated receptor/ion channels, through the application of recombinant DNA methods, is not just an academic exercise to effect evolutionary comparisons with the sequences of the corresponding vertebrate receptors. The isolation of DNA clones would provide the tools to investigate the exact locations and functional properties of these neurotransmitter receptors within simple nervous systems. In addition, since GABA receptors, at least, have been suggested to be the targets of certain pesticides, the availability of invertebrate receptor cDNAs might provide the agrochemical industry with the basis for 'high-throughput' screening methods for novel pesticidal compounds. Recently, the isolation of molluscan and Drosophila GABA receptor and glutamate receptor cDNAs, and the pharmacological properties of a GABA receptor expressed from one of these clones, have been reported. These studies should stimulate further research into the electrophysiology and pharmacology of native invertebrate ion channel proteins.

Animals↗
PubMed1992

Differential expression of GABAA/benzodiazepine receptor beta 1, beta 2, and beta 3 subunit mRNAs in the developing mouse cerebellum.

Gamma aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the mammalian cerebellum. Cerebellar granule, Purkinje, and deep nuclear neurons are known to receive GABAergic afferents. Since GABA exerts its inhibitory effects via GABA receptors, it is of interest to determine the temporal relationship between the formation of GABAergic synapses and the expression of genes coding for the GABA receptor. In a previous study, we have examined the developmental expression of binding sites for [3H]muscimol, which binds with high affinity to the beta subunits of the GABAA/benzodiazepine (GABAA/BZ) receptor. In the present study, [35S]cRNA probes were used to examine the appearance and distribution of GABAA/BZ beta 1, beta 2, and beta 3 subunit mRNAs in the developing C57BL/6 mouse cerebellum by in situ hybridization. In the adult cerebellum, the distribution of the three subunit mRNAs was clearly different, despite considerable overlap, and their temporal expression differed throughout postnatal development. The beta 1 hybridization signal appeared within the cerebellar cortex during the second postnatal week as a discrete band at the interface of the molecular and granule cell layers. Grains were distributed diffusely over small densely staining cells surrounding the Purkinje cells; relatively few grains were visible over Purkinje cell bodies themselves. This distribution may reflect an association with Bergmann glia or basket cells. The beta 2 and beta 3 hybridization signals were present considerably earlier than that of the beta 1 mRNA. The beta 2 signal was present at birth in the molecular/Purkinje cell layer; as development progressed, the signal became increasingly intense over both granule and Purkinje cells. At birth, the beta 3 subunit mRNA was present in the external germinal and molecular layers, later becoming largely localized within the granule cell layer. Dense beta 2 and beta 3 cRNA probe labeling was present over the adult granule cell layer. Moderate levels of beta 2 signal were seen over Purkinje cell bodies; considerably less labeling was observed with the beta 3 probe. The adult distribution of beta 2 and beta 3 cRNA probes showed good spatial correspondence with the known GABAA receptor beta subunit markers, [3H]-muscimol and the mAb 62-3G1 antibody, each being present within the granule cell layer. Our results indicate that the temporal expression of GABAA/BZ receptor beta subunit messages within a given cell type may be independently regulated, and that acquisition of the beta 2 and beta 3 mRNAs occurs before these cells become integrated into mature synaptic circuits.

Animals↗
PubMed2026

Add-on treatment with vinpocetine reduces seizure frequency and improves comorbidities in patients with loss-of-function γ-aminobutyric acid type A receptor variants.

OBJECTIVE: The semisynthetic compound vinpocetine has gained attention as a potential precision medicine for developmental and epileptic encephalopathies caused by loss-of-function (LoF) variants in γ-aminobutyric acid type A (GABAA) receptor genes. As a positive allosteric modulator of GABAA receptors, case reports suggest that vinpocetine can reduce epileptiform activity and seizure frequency, while improving cognitive function in patients with GABAA receptor-related epilepsies. Here, we extend these observations with a retrospective observational study evaluating the response to vinpocetine in an additional seven patients. METHODS: Patients initiated treatment with vinpocetine between 2018 and 2025 at the Danish Epilepsy Centre or abroad. Clinical data were collected from medical records, seizure diaries, and neuropsychological assessments. The modulatory efficacy of vinpocetine was investigated using electrophysiological studies. RESULTS: Nine patients harboring eight GABAA receptor LoF variants were given add-on vinpocetine treatment. Electrophysiological analyses confirmed dose-dependent positive modulation by vinpocetine across tested variants. Six patients with a median age of 15.5 years (range = 6-29) continued treatment for a median of 24 months (range = 12-90), whereas three discontinued due to adverse effects (AEs) or lack of efficacy. The patients' level of function ranged from normal to moderate intellectual disability, psychiatric comorbidities, and behavioral disturbances. Four patients initiated vinpocetine due to uncontrolled seizures. One became seizure-free, and two experienced a 50%-55% reduction. Electroencephalograms demonstrated improved spike-wave indexes in four patients. Six showed improvement in nonseizure factors, and caregivers reported reduced aggressivity and better vocabulary in one. Vinpocetine was well tolerated, with only mild and reversible AEs reported. SIGNIFICANCE: Adjunctive vinpocetine shows promise as a targeted therapy for patients with GABAA receptor LoF variants, decreasing seizure frequency and positively impacting nonseizure factors, with only mild AEs reported. Vinpocetine may be a safe and effective therapy for patients with GABAA receptor-related epilepsies, which should be investigated further in future N-of-1 trials.

Humans↗
PubMed2026

Clinical Utility of Trio Exome Sequencing in Rwandan Children With Autism Spectrum Disorder.

INTRODUCTION: Autism spectrum disorder (ASD) is a neurodevelopmental condition with substantial genetic and phenotypic heterogeneity. However, populations of African ancestry remain underrepresented in genomic studies, limiting understanding of ASD genetic architecture. This study aimed to characterize rare, clinically relevant genetic variants in a Rwandan pediatric ASD cohort using trio-based whole-exome sequencing (WES). METHODS: Trio-based WES was performed in 31 Rwandan pediatric patients with ASD (aged 2-18 years) and their parents. Variants were analyzed using a trio-based workflow and classified according to American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines. RESULTS: Eleven candidate variants were identified in 9 of 31 patients, including four likely pathogenic variants and seven variants of uncertain significance. This resulted in a diagnostic yield of 12.9% (4/31), expanded to 29.0% when phenotypically concordant variants of uncertain significance were considered. Most likely pathogenic variants were identified in individuals with syndromic ASD who presented with intellectual disability, epilepsy, and global developmental delay. Likely pathogenic findings included two single nucleotide variants in GABRB3, SYNGAP1, and two copy-number variants involving the GNAS locus and chromosome 1p35.3-p35.2. CONCLUSIONS: The diagnostic yield observed in this cohort is consistent with previous trio-based WES studies of ASD. The findings support the clinical utility of WES for the genetic evaluation of ASD and underscore the need for expanded genomic studies in African populations.

Humans↗
PubMed1992

Penicillin-induced triphasic modulation of GABAA receptor-operated chloride current in frog sensory neuron.

Effects of penicillin-G (PCN) on GABA-evoked Cl- current (IGABA) were investigated in freshly dissociated frog sensory neurons by the use of the concentration-clamp technique combined with the suction-pipette method. Under conditions where the internal and external solutions allowed only Cl- permeability, PCN elicited triphasic modulation on IGABA, consisting of two modes of blockade on IGABA and a following rebound (rebound-like transient IGABA). Simultaneously applied PCN and GABA depressed IGABA immediately (phasic blockade), with the depressed IGABA slightly recovering in amplitude to achieve a stable level of blockade (tonic blockade). When a solution containing a mixture or PCN and GABA was quickly replaced by one containing GABA alone, a rebound-like transient Cl- current (IR) was evoked. Each component of the PCN actions on IGABA was PCN- and GABA-concentration-dependent. The reversal potential for each component of the PCN actions on IGABA was close to the chloride equilibrium potential (ECl) calculated using the Nernst equation. The current-voltage (I-V) relations for both the phasic and tonic blockade revealed inward rectification, while I-V curves for the control IGABA and the IR were outwardly rectified. The degree of IGABA-desensitization and the amplitude of the IR correlated well. The data suggest that partial removal of the GABAA receptor-desensitization may result in generation of the IR.

Animals↗
PubMed1992

Ethanol modulation of GABA receptor-activated Cl- currents in neurons of the chick, rat and mouse central nervous system.

Modulation of gamma-aminobutyric acidA (GABAA) receptor function by drugs such as ethanol may depend on the genetic heterogeneity of GABAA receptor subunits, which vary across species and cell types. For this reason, the effects of ethanol on gamma-aminobutyric acid receptor-activated chloride currents (IGABA) were examined using whole-cell voltage-clamp recordings in primary cultures of neurons obtained from different species (chick, mouse and rat) and from different brain regions (cerebral cortex, hippocampus, cerebellum and spinal cord), and in acutely dissociated neurons from rat neocortical slices. Low concentrations (1-50 mM) of ethanol produced an enhancement of IGABA in some cells from each brain region examined. In cells obtained from the rat and chick cerebral cortex, 40-58% of cells exhibited an ethanol-sensitive IGABA. Moreover, a statistically significant variation in the response to ethanol was found in rat cortical neurons obtained from different litters. In mouse hippocampal neurons, potentiation of IGABA was obtained with ethanol concentrations (1-10 mM) well below those needed to inhibit neuronal responses to N-methyl-D-aspartic acid (30-50 mM), suggesting a differential sensitivity of these two receptor mechanisms to ethanol. Potentiation of IGABA by ethanol was reversed by the benzodiazepine receptor partial inverse agonist RO15-4513 (ethyl 8-azido-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine - 3-carboxylate), but was not affected by chelation of intracellular calcium. Furthermore, high concentrations of GABA attenuated the ability of ethanol to enhance IGABA. These results are consistent with the hypothesis that ethanol facilitates coupling between receptor binding and chloride channel activation.

Animals↗
PubMed1992

Developmental profile of polyadenylated and non-polyadenylated GABAA receptor subunit mRNAs.

The ratio of mRNA not selected for polyadenylation (non-poly(A)+ selected) to mRNA selected for polyadenylation (poly(A)+) for the beta 1, alpha 1 and gamma 2 subunits of the GABAA receptor complex was examined in rats as a function of age. RNA was extracted from whole brain of rats that were either 0, 1, 3, 5 or over 60 days of postnatal age. Poly(A)+ mRNA was purified by oligo(dT)-cellulose chromatography. Non-poly(A)+ selected mRNA and poly(A)+ mRNA for the GABAA receptor beta 1, alpha 1 and gamma 2 subunits were examined by Northern blot analysis using cDNA probes specific for these subunits. Levels of GABAA receptor beta 1 subunit mRNA were also examined by solution hybridization analysis with a beta 1 riboprobe. Analysis of Northern blots revealed that levels of poly(A)+ beta 1 subunit mRNA were highest at 0 days of age, but decreased and reached adult levels by 5 days of postnatal age. However, levels of the beta 1 subunit message extracted from non-poly(A)+ selected mRNA were not significantly different at any of the ages examined, suggesting the existence of a population of beta 1 subunit mRNA that is not polyadenylated. The age-related discrepancy between beta 1 subunit levels measured in non-poly(A)+ selected mRNA and poly(A)+ mRNA was also observed using solution hybridization analysis. In contrast, levels of both non-poly(A)+ selected mRNA and poly(A)+ mRNA for the alpha 1 subunit of the GABAA complex increased from 0 days of age to adulthood. Similarly, levels of both non-poly(A)+ selected mRNA and poly(A)+ mRNA for the GABAA receptor gamma 2 subunit increased with age.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMed1992

Molecular and electrophysiological characterization of a allelic variant of the rat alpha 6 GABAA receptor subunit.

A 1.45 kb DNA sequence encoding the rat alpha 6 GABAA receptor subunit (nucleotides 33-1483) was cloned from a Sprague-Dawley rat brain cDNA library by PCR amplification. Dideoxy sequencing of two individual clones revealed that the nucleotide sequence differed at only one basepair (T480-->G) from that published previously. This difference altered the deduced amino acid sequence, producing a conservative amino acid substitution (His121-->Gln). A Gln residue is present at the same location in the bovine alpha 6 subunit. Restriction endonuclease analysis of the total PCR product demonstrated that this variant of the rat alpha 6 subunit was the only allele found in this particular rat brain library, the original allele was not present. These results were further verified by RNAse protection assays performed with RNA isolated from individual rat cerebella. alpha 6, beta 1, and gamma 2S subunits were transiently expressed in L929 cells for electrophysiological analysis. Whole-cell recordings obtained from the cells demonstrated that GABAA receptor channels with the expected GABA and benzodiazepine pharmacology were produced. Excised outside out single channel recordings from the same cells revealed that GABA elicited brief duration openings to a 33 pS main conductance level and to at least one smaller (approximately 21 pS) subconductance level. Thus this allelic variant of rat alpha 6 subunit could assemble with other subunits to form a functional GABAA receptor channel with similar properties to the original allelic form.

Alleles↗
PubMed1992

Selective potentiation of GABA-mediated Cl- current by lanthanum ion in subtypes of cloned GABAA receptors.

The effect of lanthanum ion (La3+) on gamma-aminobutyric acid (GABA)-mediated Cl- currents was examined in the alpha 1 beta 2 or alpha 1 beta 2 gamma 2 subtype of GABAA receptors expressed in a human kidney cell line (A293), using a whole-cell configuration of patch-clamp techniques. La3+ dose-dependently stimulated the Cl- currents in the alpha 1 beta 2 gamma 2 subtype with an EC50 of 21.3 +/- 3.5 microM with a maximal potentiation of 240 +/- 16% as normalized to the GABA response at 5 microM. In the alpha 1 beta 2 subtype, however, the ion marginally potentiated GABA response, a maximal stimulation being less than 70% with an EC50 for La3+ near 200 microM. The stimulation of GABA response by La3+ in the alpha 1 beta 2 gamma 2 subtype was due to a decrease in the half maximal concentration for GABA and was more pronounced at the negative membrane potentials. This selectivity of La3+ toward the subtypes of GABAA receptors contrasts to that of Zn2+ which inhibits the currents in the alpha 1 beta 2, but not in the alpha 1 beta 2 gamma 2 subtype (Neuron, 5: (1990) 781-788). It appears that these polyvalent cations are useful in understanding the molecular basis for the functional diversity and in characterizing the molecular organization of native GABAA receptors.

Cell Line↗
PubMed1992

Modulation of GABAA receptor-activated current by norepinephrine in cerebellar Purkinje cells.

Previous studies employing extracellular single-unit recording in the intact cerebellum have demonstrated that norepinephrine can potentiate GABA-induced suppression of Purkinje cell spike activity. However, many issues related to the nature of this modulatory phenomenon remain to be resolved. Using whole-cell patch clamp recording, the present study investigated the effect of norepinephrine on GABA-activated membrane currents (IGABA) in solitary Purkinje cells isolated from neonatal rat cerebella following acute dissociation. Exposure of Purkinje cells to norepinephrine at a concentration which, by itself, had no obvious effect on Purkinje cell membrane conductance, consistently augmented IGABA. The catecholamine also potentiated GABA-gated chloride currents as well as muscimol-induced currents in Purkinje cells. Thus, the facilitating effect of norepinephrine on IGABA was attributed to an interaction between norepinephrine and the GABAA receptor-mediated chloride conductance. The effect of norepinephrine could be mimicked by isoproterenol as well as by 8-bromo cAMP, suggesting that a beta-receptor-mediated, cAMP-dependent cascade may underlie the observed heteroreceptor interaction. Our results establish the existence of a postsynaptic mechanism by which norepinephrine, through activation of the beta-adrenoceptor, may modulate GABAA receptor function in cerebellar Purkinje cells. This study provides the groundwork for a detailed investigation into the cascade of membrane and intracellular events underlying such a synergistic modulatory interaction at the cellular and subcellular levels.

Animals↗
PubMed1992

Sodium and GABA-activated channels as the targets of pyrethroids and cyclodienes.

The symptoms of poisoning by the pyrethroid and cyclodiene insecticides are characterized by hyperexcitation and convulsions followed by paralysis. The main target site of the pyrethroids has been identified to be the sodium channels which are kept open for unusually long periods of time, causing a prolonged sodium current to flow which, in turn, leads to hyperexcitation of the nervous system. We have now found large differential sensitivity to the pyrethroids in two types of sodium channels. The dorsal root ganglion neurons of the rat were endowed with two types of sodium channels, one sensitive to the blocking action of tetrodotoxin (TTX) and the other insensitive to TTX. The type I pyrethroid allethrin and the type II pyrethroid deltamethrin were both effective in prolonging the sodium current in the TXX-resistant sodium channel but had only a small effect on the TTX-sensitive sodium channel. These two types of sodium channels also exhibited marked differences in their physiological properties, including the time course of current, the activation voltage, and the steady-state inactivation. In contrast to the pyrethroids, lindane and the cyclodienes endrin, isobenzan, dieldrin and heptachlor-epoxide suppressed the GABA-induced chloride current. The initial transient component of the chloride current was blocked more than the late sustained component. The suppression of the GABA-mediated synaptic inhibition would cause hyperexcitation of the nervous system. The results are compatible with the convulsant action of these insecticides.

Animals↗
PubMed2025

Functional synapses between neurons and small cell lung cancer.

Small cell lung cancer (SCLC) is a highly aggressive type of lung cancer, characterized by rapid proliferation, early metastatic spread, frequent early relapse and a high mortality rate1-3. Recent evidence has suggested that innervation has an important role in the development and progression of several types of cancer4,5. Cancer-to-neuron synapses have been reported in gliomas6,7, but whether peripheral tumours can form such structures is unknown. Here we show that SCLC cells can form functional synapses and receive synaptic transmission. Using in vivo insertional mutagenesis screening in conjunction with cross-species genomic and transcriptomic validation, we identified neuronal, synaptic and glutamatergic signalling gene sets in mouse and human SCLC. Further experiments revealed the ability of SCLC cells to form synaptic structures with neurons in vitro and in vivo. Electrophysiology and optogenetic experiments confirmed that cancer cells can receive NMDA receptor- and GABAA receptor-mediated synaptic inputs. Fitting with a potential oncogenic role of neuron-SCLC interactions, we showed that SCLC cells derive a proliferation advantage when co-cultured with vagal sensory or cortical neurons. Moreover, inhibition of glutamate signalling had therapeutic efficacy in an autochthonous mouse model of SCLC. Therefore, following malignant transformation, SCLC cells seem to hijack synaptic signalling to promote tumour growth, thereby exposing a new route for therapeutic intervention.

Animals↗
PubMed1992

[The clinico-hemodynamic effects of the activator of the GABA-ergic stress-limiting system sodium valproate (acediprol) and etatsizin in patients with cardiac arrhythmias].

Hemodynamic and antiarrhythmic effects of acediprol and ethacizine were examined in 51 patients with premature ventricular contraction concurrent with neurocirculatory dystonia and coronary heart disease. It was ascertained that acediprol exerted a positive inotropic action and ethacizine lowered myocardial contractility. Acediprol therapy prevents or attenuates the hypokinetic and arrhythmogenic effects of stimulated stress in patients with ischemic and non-ischemic arrhythmias. The preventive antiarrhythmic effect of acediprol is the most pronounced in patients with neurocirculatory dystonia. Ethacizine fails to improve hemodynamic supply of the stress test and enhances stress-related hypodynamia in some patients.

Anti-Arrhythmia Agents↗