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Different subtypes of GABA-A receptors are expressed in human, mouse and rat T lymphocytes
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology. (Bryndis Birnir)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology. (Bryndis Birnir)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology. (Bryndis Birnir)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
2012 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 8, e42959- p.Article in journal (Refereed) Published
Abstract [en]

γ-aminobutyric acid (GABA) is the most prominent neuroinhibitory transmitter in the brain, where it activates neuronalGABA-A receptors (GABA-A channels) located at synapses and outside of synapses. The GABA-A receptors are primarytargets of many clinically useful drugs. In recent years, GABA has been shown to act as an immunomodulatory molecule. Wehave examined in human, mouse and rat CD4+ and CD8+ T cells which subunit isoforms of the GABA-A channels areexpressed. The channel physiology and drug specificity is dictated by the GABA-A receptor subtype, which in turn isdetermined by the subunit isoforms that make the channel. There were 5, 8 and 13 different GABA-A subunit isoformsidentified in human, mouse and rat CD4+ and CD8+ T cells, respectively. Importantly, the γ2 subunit that imposesbenzodiazepine sensitivity on the GABA-A receptors, was only detected in the mouse T cells. Immunoblots andimmunocytochemistry showed abundant GABA-A channel proteins in the T cells from all three species. GABA-activatedwhole-cell transient and tonic currents were recorded. The currents were inhibited by picrotoxin, SR95531 and bicuculline,antagonists of GABA-A channels. Clearly, in both humans and rodents T cells, functional GABA-A channels are expressed butthe subtypes vary. It is important to bear in mind the interspecies difference when selecting the appropriate animal modelsto study the physiological role and pharmacological properties of GABA-A channels in CD4+ and CD8+ T cells and whenselecting drugs aimed at modulating the human T cells function.

Place, publisher, year, edition, pages
2012. Vol. 7, no 8, e42959- p.
National Category
Neurosciences
Identifiers
URN: urn:nbn:se:uu:diva-172532DOI: 10.1371/journal.pone.0042959ISI: 000307789700016OAI: oai:DiVA.org:uu-172532DiVA: diva2:514878
Available from: 2012-04-11 Created: 2012-04-11 Last updated: 2017-12-07Bibliographically approved
In thesis
1. Role of GABA and GABAA Channels in T lymphocytes and Stem cells
Open this publication in new window or tab >>Role of GABA and GABAA Channels in T lymphocytes and Stem cells
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

GABA (gamma-aminobutyric acid) is best known for its physiological function in the central nervous system.  In the brain GABA is the main inhibitory neurotransmitter where it decreases excitability of neurons and neuronal networks.  The balance between excitation evoked by glutamate and inhibition evoked by GABA is the base from where the brain works. It is fair to say that glutamate is like the gas-pedal and GABA the brake that keeps the brain running at a normal speed.  But, it is not only in the brain that GABA is taking a part in a physiological process vital to life. GABA is present in blood and is even released in the pancreatic islets. What function GABA has in these tissues is still being examined and is the focus of this thesis. The GABA concentration in the peripheral tissues is in the submicromolar concentration range. 

The studies in this thesis support the idea that GABA reduces the proliferation and cytokine secretion from immune cells by activating high-affinity GABAA channels in the cells. In contrast, in retinal progenitor stem cells GABA promotes cell proliferation.  These studies demonstrate that the effect of GABA on proliferation is cell-type specific. The GABAA channel subunit isoforms expressed in human, mice and rats T cells differ between the species.  This interspecies variability will result in different pharmacological profile of the subtypes of GABAA channels expressed whereas the physiological process most likely is the same.  Clearly, GABA is not only a neurotransmitter molecule but is also an immunomodulator and an important signal molecule in peripheral tissues. 

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2012. 60 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 768
National Category
Neurosciences Physiology
Identifiers
urn:nbn:se:uu:diva-172541 (URN)978-91-554-8348-7 (ISBN)
Public defence
2012-05-28, C4 :301, BMC, Husargatan 3, Uppsala, 13:00 (English)
Supervisors
Available from: 2012-05-07 Created: 2012-04-11 Last updated: 2012-08-01Bibliographically approved

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