Brain chemical GABA shown to trigger immune cell responses in lab studies
Researchers found that GABA—a neurotransmitter typically associated with brain function—can activate immune cells and alter their calcium levels, a key step in immune response. The discovery could open new therapeutic pathways for autoimmune and inflammatory diseases, potentially offering an alternative mechanism to current immunosuppressant drugs.
Originaltitel: GABAA receptor agonists modulate intracellular Ca2+ levels in activated human CD4+ T cells
GABA binding to GABA A receptors induces transient elevation in intracellular Ca 2+ concentrations in activated human CD4 + T cells. Here we examined the Ca 2+ response evoked by the GABA A receptor agonists THIP, muscimol, isoguvacine, and TACA and further, effects of K V 1.3 and KCa3.1 channel blockers on the GABA-evoked Ca 2+ signal. The cells were activated by anti-CD3 antibody and cultured for 72 h before the effects of agonists and antagonists on intracellular Ca 2+ levels were examined by Ca 2+ imaging. mRNA sequencing, qPCR, and immunofluorescence imaging identified the GABA A subunits expressed. Both the half-maximal concentration for activation (the apparent affinity (EC 50 )) and the evoked, peak cellular Ca 2+ response varied among the agonists. The agonists EC 50 values varied more than 1,000-fold, but the compounds can, nevertheless, all be classified as high-affinity agonists (EC 50 < 1 μM). The EC 50 sequence was as follows: GABA (0.005 nM) ≈ THIP (0.005 nM) < muscimol (0.162 nM) < TACA (2.2 nM) < isoguvacine (54.4 nM). In contrast, the peak increase in the cellular Ca 2+ signal followed the sequence: GABA >> THIP > muscimol > isoguvacine > TACA. For all agonists, the transient Ca 2+ signal was attenuated at micromolar concentrations. ShK-Dap22 and TRAM-34 that block K V 1.3 and KCa3.1 channels, respectively, inhibited the GABA-activated Ca 2+ response. The CRAC channel inhibitor YM58483 reduced the Ca 2+ current by 40%. The pharmacology is consistent with the ρ2 GABA A receptor subunit being a part of the high-affinity GABA A receptors expressed in human CD4 + T cells. The agonists at the ρ2-containing GABA A receptors induced intracellular Ca 2+ signals in human CD4 + T cells that were related to the agonist concentration. All tested agonists have a high apparent affinity but differ in efficacy at the receptors. Ca 2+ signaling enables high-throughput assays for fast screening of potential drugs aimed at GABA A receptors regulating the T cell functions.