• High data quality based on giga-ohm seal resistances in physiological solutions
• High flexibility of assay design
• Flexible voltage clamp and current clamp
• Enable discovery of new therapeutics for channelopathies
• Measure single dose as well as concentration-dependent effects
• Comparable channels recording between different physiological and disease cell models

The major inhibitory neurotransmitter of the central nervous system is γ-aminobutyric acid (GABA) and GABA is exerting its effect by binding to GABA receptors. The central role of GABA in the nervous system is underscored by the devastating consequences of pathophysiological changes in GABA signalling. Conversely, manipulation of GABA receptors can offer relief of a large group of neurological and psychiatric disorders. Pharmacological manipulation of GABAA has a large potential and ligands increasing the current will typically have anxiolytic, anticonvulsant, amnesic, sedative, hypnotic, euphoriant, and muscle relaxant effects.

GABAA receptors are ligand-gated ion channels, permeable to Cl- ions, consisting of 5 membrane-spanning subunits. 16 different subunits are identified in humans (α1-6, β1-3, γ1-3, δ, ε, θ, π) and the cellular GABA response is hence composed by a population of GABA receptors with significant different pharmacology. Here we demonstrate pharmacological GABA receptor evaluation in both a stably-transfected cell line containing only α5β3γ2 receptors and a primary cell culture of rat hippocampal astrocytes with a diverse GABA receptor population.

The major inhibitory neurotransmitter of the central nervous system is γ-aminobutyric acid (GABA) and GABA is exerting its effect by binding to GABA receptors. The central role of GABA in the nervous system is underscored by the devastating consequences of pathophysiological changes in GABA signalling. Conversely, manipulation of GABA receptors can offer relief of a large group of neurological and psychiatric disorders. Pharmacological manipulation of GABAA has a large potential and ligands increasing the current will typically have anxiolytic, anticonvulsant, amnesic, sedative, hypnotic, euphoriant, and muscle relaxant effects^1–4.
GABAA receptors are ligand-gated ion channels, permeable to Cl- ions, consisting of 5 membrane-spanning subunits^5,6. 16 different subunits are identified in humans (α1-6, β1-3, γ1-3, δ, ε, θ, π) and the cellular GABA response is hence composed by a population of GABA receptors with significant different pharmacology⁷. Here we demonstrate pharmacological GABA receptor evaluation in both a stably-transfected cell line containing only α5β3γ2 receptors and a primary cell culture of rat hippocampal astrocytes with a diverse GABA receptor population.

Substantial efforts have been recently committed to develop coronavirus disease-2019 (COVID-19) medications, and Hydroxychloroquine alone or in combination with Azithromycin has been promoted as a repurposed treatment. Although these drugs may increase cardiac toxicity risk, cardiomyocyte mechanisms underlying this risk remain poorly understood in humans. Therefore, we evaluated the proarrhythmia risk and inotropic effects of these drugs in the cardiomyocyte contractility-based model of the human heart. We found Hydroxychloroquine to have a low proarrhythmia risk, whereas Chloroquine and Azithromycin were associated with high risk. Hydroxychloroquine proarrhythmia risk changed to high with low level of K⁺, whereas high level of Mg²⁺ protected against proarrhythmic effect of high Hydroxychloroquine concentrations. Moreover, therapeutic concentration of Hydroxychloroquine caused no enhancement of elevated temperature-induced proarrhythmia. Polytherapy of Hydroxychloroquine plus Azithromycin and sequential application of these drugs were also found to influence proarrhythmia risk categorization. Hydroxychloroquine proarrhythmia risk changed to high when combined with Azithromycin at therapeutic concentration. However, Hydroxychloroquine at therapeutic concentration impacted the cardiac safety profile of Azithromycin and its proarrhythmia risk only at concentrations above therapeutic level. We also report that Hydroxychloroquine and Chloroquine, but not Azithromycin, decreased contractility while exhibiting multi-ion channel block features, and Hydroxychloroquine’s contractility effect was abolished by Azithromycin. Thus, this study has the potential to inform clinical studies evaluating repurposed therapies, including those in the COVID-19 context. Additionally, it demonstrates the translational value of the human cardiomyocyte contractility-based model as a key early discovery path to inform decisions on novel therapies for COVID-19, malaria, and inflammatory diseases.