GABAA receptor plasticity in Jurkat T cells

Dionisio, Leonardo Raul; Arias, Verónica; Bouzat, Cecilia; Esandi, María del Carmen

doi:10.1016/j.biochi.2013.08.023

Cited by 8 publications

(12 citation statements)

References 29 publications

(40 reference statements)

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“…The cells in our experiments were incubated at high density as described in the Materials and Methods. Taking into account our observation of GAD2 expression alongside the observations of others [ 47 , 48 ] we speculate that the concentration of GABA in the culture medium may reach sufficient levels to act together with benzodiazepines on GABA (A)Rs. It is our intention to investigate this phenomenon further.…”

Section: Discussionsupporting

confidence: 76%

“…According to Bhandage et al, 2020 [ 47 ] human and mouse myeloid mononuclear cells are capable of producing GABA. Moreover, Dionisio et al, 2013 [ 48 ] identified GAD67, one of the GABA producing enzymes in Jurkat T cells. Our own observations presented on Fig 1B indicate strong expression of GAD2 that encodes the GAD65 enzyme in human T cells.…”

Section: Discussionmentioning

confidence: 99%

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Activation of GABA(A) receptors inhibits T cell proliferation

et al. 2021

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Background The major sites for fast synaptic inhibition in the central nervous system (CNS) are ion channels activated by γ-aminobutyric acid (GABA). These receptors are referred as GABA(A) receptors (GABA(A)R). Recent evidence indicates a role of GABA(A)R in modulating the immune response. This work aimed to discern the role of GABA and GABA(A)Rs in human and mouse T cell activity. Methods Mouse splenocytes or human peripheral blood mononuclear cells (PBMCs) were activated with anti-CD3 antibodies and the proliferation of both CD8+ and CD4+ T cells assessed through flow cytometry. Subsequently, the effects on T cell proliferation of either GABA(A)R modulation by diazepam that is also capable of activating mitochondrial based translocator protein (TSPO), alprazolam and allopregnanolone or inhibition by bicucculine methiodide (BMI) and (1,2,5,6-Tetrahydropyridin-4-yl)methylphosphinic acid (TPMPA) were assessed. Results Positive modulation of GABA(A)Rs either by benzodiazepines or the neurosteroid allopregnanolone inhibits both mouse and human T cell proliferation. GABAergic inhibition of T cell proliferation by benzodiazepines could be rescued by GABA(A)R blocking. Our data suggest that benzodiazepines influence T cell proliferation through both TSPO and GABA(A)Rs activation. Conclusions We conclude that activation of GABA(A)Rs provides immunosuppression by inhibiting T cell proliferation.

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Section: Discussionsupporting

confidence: 76%

Section: Discussionmentioning

confidence: 99%

Activation of GABA(A) receptors inhibits T cell proliferation

et al. 2021

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“…This is counteracting T cell activation, which has been shown to increase intracellular Cl - levels 47 to promote store-operated Ca 2+ entry. 48 GABA at a concentration of 100 μM has been shown to depolarize Jurkat cells, 41 however concentrations as low as 1 μM GABA were found sufficient to evoke current changes in combination with GABA A R antagonist ER95531. 22 Herein, we report for the first time the EC 50 for Jurkat cells to be 3.1 μM for GABA.…”

Section: Discussionmentioning

confidence: 96%

Development of GABA_A Receptor Subtype-Selective Imidazobenzodiazepines as Novel Asthma Treatments

et al. 2016

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Recent studies have demonstrated that subtype-selective GABAA receptor modulators are able to relax pre-contracted human airway smooth muscle ex vivo and reduce airway hyper-responsiveness in mice upon aerosol administration. Our goal in this study was to investigate systemic administration of subtype-selective GABAA receptor modulators to alleviate bronchoconstriction in a mouse model of asthma. Expression of GABAA receptor subunits was identified in mouse lungs and the effects of α4-subunit-selective GABAAR modulators, XHE-III-74EE and its metabolite XHE-III-74A, were investigated in a murine model of asthma (ovalbumin sensitized and challenged BALB/c mice). We observed that chronic treatment with XHE-III-74EE significantly reduced airway hyper-responsiveness. In addition, acute treatment with XHE-III-74A but not XHE-III-74EE decreased airway eosinophilia. Immune suppressive activity was also shown in activated human T-cells with a reduction in IL-2 expression and intracellular calcium concentrations [Ca2+]i in the presence of GABA or XHE-III-74A, whereas XHE-III-74EE showed only partial reduction of [Ca2+]i and no inhibition of IL-2 secretion. However, both compounds significantly relaxed pre-contracted tracheal rings ex vivo. Overall, we conclude that the systemic delivery of a α4-subunit-selective GABAAR modulator shows good potential for a novel asthma therapy, however, the pharmacokinetic properties of this class of drug candidates have to be improved to enable better beneficial systemic pharmacodynamic effects.

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“…() and Dionisio et al . (, ) isolated T cells from peripheral blood and identified three ( α 1, α 3 and β 2) and seven ( α 1, α 3, α 6, β 3, γ 2, δ and ρ 2) different GABA‐A subunits respectively. Mendu et al .…”

Section: Gaba‐activated Receptors In T Cellsmentioning

confidence: 99%

GABAergic signalling in the immune system

et al. 2015

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The GABAergic system is the main inhibitory neurotransmitter system in the central nervous system (CNS) of vertebrates. Signalling of the transmitter γ-aminobutyric acid (GABA) via GABA type A receptor channels or G-protein-coupled type B receptors is implicated in multiple CNS functions. Recent findings have implicated the GABAergic system in immune cell functions, inflammatory conditions and diseases in peripheral tissues. Interestingly, the specific effects may vary between immune cell types, with stage of activation and be altered by infectious agents. GABA/GABA-A receptor-mediated immunomodulatory functions have been unveiled in immune cells, being present in T lymphocytes and regulating the migration of Toxoplasma-infected dendritic cells. The GABAergic system may also play a role in the regulation of brain resident immune cells, the microglial cells. Activation of microglia appears to regulate the function of GABAergic neurotransmission in neighbouring neurones through changes induced by secretion of brain-derived neurotrophic factor. The neurotransmitter-driven immunomodulation is a new but rapidly growing field of science. Herein, we review the present knowledge of the GABA signalling in immune cells of the periphery and the CNS and raise questions for future research.

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GABAA receptor plasticity in Jurkat T cells

Cited by 8 publications

References 29 publications

Activation of GABA(A) receptors inhibits T cell proliferation

Activation of GABA(A) receptors inhibits T cell proliferation

Development of GABA_A Receptor Subtype-Selective Imidazobenzodiazepines as Novel Asthma Treatments

GABAergic signalling in the immune system

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GABAA receptor plasticity in Jurkat T cells

Cited by 8 publications

References 29 publications

Activation of GABA(A) receptors inhibits T cell proliferation

Activation of GABA(A) receptors inhibits T cell proliferation

Development of GABAA Receptor Subtype-Selective Imidazobenzodiazepines as Novel Asthma Treatments

GABAergic signalling in the immune system

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Product

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Development of GABA_A Receptor Subtype-Selective Imidazobenzodiazepines as Novel Asthma Treatments