Activation of GABA(A) receptors inhibits T cell proliferation

Abstract

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.

Structure–Activity Studies of 3,9-Diazaspiro[5.5]undecane-Based γ-Aminobutyric Acid Type A Receptor Antagonists with Immunomodulatory Effect

“…Although at the high concentration tested, 1e moderately binds to the α7 nACh and to the 5-HT3 receptors, these are only faintly expressed in T cells according to various databases (, , ) . This information, combined with the high expression levels of GABA A Rs in T cells, the high GABA A R potency of 1e , and a very specific antiproliferative effect induced by benzodiazepine alprazolam reverted by two chemically diverse GABA A Rs antagonists 1e and BMI, strongly suggests a GABA A R-mediated effect of 1e .…”

“…org). 51 This information, combined with the high expression levels of GABA A Rs in T cells, 52 the high GABA A R potency of 1e, and a very specific antiproliferative effect induced by benzodiazepine alprazolam reverted by two chemically diverse GABA A Rs antagonists 1e and BMI, strongly suggests a GABA A R-mediated effect of 1e.…”

Dysregulation of β-Cell Proliferation in Diabetes: Possibilities of Combination Therapy in the Development of a Comprehensive Treatment

“…In rodent models, GABA treatment reduced circulating inflammatory cytokines including IL-1β, TNF-α, IFN-γ, and IL-12 in STZ-induced mice, and in vitro, GABA reduced CD4+ and CD8+ T cells and increased regulatory T cells [ 103 ]. Furthermore, the activation of GABA(A) receptor has been shown to inhibit proliferation in T cells isolated from human peripheral blood mononuclear cells in vitro [ 106 ]. Based on these compelling data, clinical trials with GABA have been initiated for prevention and treatment for new onset T1DM; however, its safety and efficacy has not been reported thus far [ 107 ].…”

Downregulation of miR-185 is a common pathogenic event in 22q11.2 deletion syndrome-related and idiopathic schizophrenia

“…GABA is considered the main inhibitory neurotransmitter inside the central nervous system (CNS). GABA acts via two subclasses of receptors, GABA A receptors (GABA A Rs) and GABA B Rs (Sparrow et al 2021). GABA A Rs are ligand-gated ion channels, also called ionotropic receptors; whereas GABA B Rs are G protein-coupled receptors (also known as metabotropic receptors) (Sparrow et al 2021).…”

“…GABA acts via two subclasses of receptors, GABA A receptors (GABA A Rs) and GABA B Rs (Sparrow et al 2021). GABA A Rs are ligand-gated ion channels, also called ionotropic receptors; whereas GABA B Rs are G protein-coupled receptors (also known as metabotropic receptors) (Sparrow et al 2021). The GABA is now considered an actor beyond the realm of CNS, in contrast with the previously supposed role of neuronal behavior regulator.…”