{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T05:11:12Z","timestamp":1778217072981,"version":"3.51.4"},"reference-count":43,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T00:00:00Z","timestamp":1778198400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"\n GABA binding to GABA\n A<\/jats:sub>\n receptors induces transient elevation in intracellular Ca\n 2+<\/jats:sup>\n concentrations in activated human CD4\n +<\/jats:sup>\n T cells. Here we examined the Ca\n 2+<\/jats:sup>\n response evoked by the GABA\n A<\/jats:sub>\n receptor agonists THIP, muscimol, isoguvacine, and TACA and further, effects of K\n V<\/jats:sub>\n 1.3 and KCa3.1 channel blockers on the GABA-evoked Ca\n 2+<\/jats:sup>\n signal. The cells were activated by anti-CD3 antibody and cultured for 72\u00a0h before the effects of agonists and antagonists on intracellular Ca\n 2+<\/jats:sup>\n levels were examined by Ca\n 2+<\/jats:sup>\n imaging. mRNA sequencing, qPCR, and immunofluorescence imaging identified the GABA\n A<\/jats:sub>\n subunits expressed. Both the half-maximal concentration for activation (the apparent affinity (EC\n 50<\/jats:sub>\n )) and the evoked, peak cellular Ca\n 2+<\/jats:sup>\n response varied among the agonists. The agonists EC\n 50<\/jats:sub>\n values varied more than 1,000-fold, but the compounds can, nevertheless, all be classified as high-affinity agonists (EC\n 50<\/jats:sub>\n &lt; 1 \u03bcM). The EC\n 50<\/jats:sub>\n sequence was as follows: GABA (0.005 nM) \u2248 THIP (0.005 nM) &lt; muscimol (0.162 nM) &lt; TACA (2.2 nM) &lt; isoguvacine (54.4 nM). In contrast, the peak increase in the cellular Ca\n 2+<\/jats:sup>\n signal followed the sequence: GABA &gt;&gt; THIP &gt; muscimol &gt; isoguvacine &gt; TACA. For all agonists, the transient Ca\n 2+<\/jats:sup>\n signal was attenuated at micromolar concentrations. ShK-Dap22 and TRAM-34 that block K\n V<\/jats:sub>\n 1.3 and KCa3.1 channels, respectively, inhibited the GABA-activated Ca\n 2+<\/jats:sup>\n response. The CRAC channel inhibitor YM58483 reduced the Ca\n 2+<\/jats:sup>\n current by 40%. The pharmacology is consistent with the \u03c12 GABA\n A<\/jats:sub>\n receptor subunit being a part of the high-affinity GABA\n A<\/jats:sub>\n receptors expressed in human CD4\n +<\/jats:sup>\n T cells. The agonists at the \u03c12-containing GABA\n A<\/jats:sub>\n receptors induced intracellular Ca\n 2+<\/jats:sup>\n signals in human CD4\n +<\/jats:sup>\n 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\n 2+<\/jats:sup>\n signaling enables high-throughput assays for fast screening of potential drugs aimed at GABA\n A<\/jats:sub>\n receptors regulating the T cell functions.\n <\/jats:p>","DOI":"10.3389\/fimmu.2026.1693150","type":"journal-article","created":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T04:48:20Z","timestamp":1778215700000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["GABAA receptor agonists modulate intracellular Ca2+ levels in activated human CD4+ T cells"],"prefix":"10.3389","volume":"17","author":[{"given":"Sergiy V.","family":"Korol","sequence":"first","affiliation":[{"name":"Department of Medical Cell Biology, Uppsala University","place":["Uppsala, Sweden"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhe","family":"Jin","sequence":"additional","affiliation":[{"name":"Department of Medical Cell Biology, Uppsala University","place":["Uppsala, Sweden"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amol K.","family":"Bhandage","sequence":"additional","affiliation":[{"name":"Department of Medical Cell Biology, Uppsala University","place":["Uppsala, Sweden"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hayma","family":"Hammoud","sequence":"additional","affiliation":[{"name":"Department of Medical Cell Biology, Uppsala University","place":["Uppsala, Sweden"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bryndis","family":"Birnir","sequence":"additional","affiliation":[{"name":"Department of Medical Cell Biology, Uppsala University","place":["Uppsala, Sweden"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,5,8]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1124\/pr.108.00505","article-title":"International union of pharmacology. 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