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Role of GABA and GABAA Channels in T lymphocytes and Stem cells
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. (Bryndis Birnir)
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: urn:nbn:se:uu:diva-172541ISBN: 978-91-554-8348-7 (print)OAI: oai:DiVA.org:uu-172541DiVA: diva2:514916
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
List of papers
1. GABA, a natural immunomodulator of T lymphocytes
Open this publication in new window or tab >>GABA, a natural immunomodulator of T lymphocytes
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2008 (English)In: Journal of Neuroimmunology, ISSN 0165-5728, E-ISSN 1872-8421, Vol. 205, no 1-2, 44-50 p.Article in journal (Refereed) Published
Abstract [en]

gamma-aminobutyric acid (GABA) is the main neuroinhibitory transmitter in the brain. Here we show that GABA in the extracellular space may affect the fate of pathogenic T lymphocytes entering the brain. We examined in encephalitogenic T cells if they expressed functional GABA channels that could be activated by the low (nM-1 microM), physiological concentrations of GABA present around neurons in the brain. The cells expressed the alpha1, alpha4, beta2, beta3, gamma1 and delta GABAA channel subunits and formed functional, extrasynaptic-like GABA channels that were activated by 1 microM GABA. 100 nM and higher GABA concentrations decreased T cell proliferation. The results are consistent with GABA being immunomodulatory.

Place, publisher, year, edition, pages
Elsevier, 2008
Keyword
GABAA, Tonic current, Inhibition, T cell
National Category
Physiology
Identifiers
urn:nbn:se:uu:diva-172499 (URN)10.1016/j.jneuroim.2008.08.017 (DOI)18954912 (PubMedID)
Available from: 2012-04-10 Created: 2012-04-10 Last updated: 2017-12-07
2. Increased GABA(A) channel subunits expression in CD8(+) but not in CD4(+) T cells in BB rats developing diabetes compared to their congenic littermates
Open this publication in new window or tab >>Increased GABA(A) channel subunits expression in CD8(+) but not in CD4(+) T cells in BB rats developing diabetes compared to their congenic littermates
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2011 (English)In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 48, no 4, 399-407 p.Article in journal (Refereed) Published
Abstract [en]

GABA (γ-aminobutyric acid), the main inhibitory neurotransmitter in the central nervous system is also present in the pancreatic islet β cells where it may function as a paracrine molecule and perhaps as an immunomodulator of lymphocytes infiltrating the pancreatic islet. We examined CD4(+) and CD8(+) T cells from diabetes prone (DR(lyp/lyp)) or resistant (DR(+/+)) congenic biobreeding (BB) rats for expression of GABA(A) channels. Our results show that BB rat CD4(+) and CD8(+) T cells express α1, α2, α3, α4, α6, β3, γ1, δ, ρ1 and ρ2 GABA(A) channel subunits. In CD8(+) T cells from DR(lyp/lyp) animals the subunits were significantly upregulated relative to expression levels in the CD8(+) T cells from DR(+/+) rats as well as from CD4(+) T cells from both DR(lyp/lyp) and DR(+/+) rats. Functional channels were formed in the T cells and physiological concentrations of GABA (100 nM) decreased T cell proliferation. Our results are consistent with the hypothesis that GABA in the islets of Langerhans may diminish inflammation by inhibition of activated T lymphocytes.

Keyword
Diabetes, GABA, GABAA subunits, Immunomodulation, Lymphocytes, Proliferation
National Category
Medical and Health Sciences
Research subject
Physiology
Identifiers
urn:nbn:se:uu:diva-148237 (URN)10.1016/j.molimm.2010.08.005 (DOI)000286955400004 ()21112637 (PubMedID)
Available from: 2011-03-03 Created: 2011-03-03 Last updated: 2017-12-11Bibliographically approved
3. Different subtypes of GABA-A receptors are expressed in human, mouse and rat T lymphocytes
Open this publication in new window or tab >>Different subtypes of GABA-A receptors are expressed in human, mouse and rat T lymphocytes
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.

National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-172532 (URN)10.1371/journal.pone.0042959 (DOI)000307789700016 ()
Available from: 2012-04-11 Created: 2012-04-11 Last updated: 2017-12-07Bibliographically approved
4. GABA maintains the proliferation of progenitors in the developing chick ciliary marginal zone and non-pigmented ciliary epithelium:      
Open this publication in new window or tab >>GABA maintains the proliferation of progenitors in the developing chick ciliary marginal zone and non-pigmented ciliary epithelium:      
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2012 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 5, e36874- p.Article in journal (Refereed) Published
Abstract [en]

GABA is more than the main inhibitory neurotransmitter found in the adult CNS. Several studies have shown that GABA regulates the proliferation of progenitor and stem cells. This work examined the effects of the GABA(A) receptor system on the proliferation of retinal progenitors and non-pigmented ciliary epithelial (NPE) cells. qRT-PCR and whole-cell patch-clamp electrophysiology were used to characterize the GABA(A) receptor system. To quantify the effects on proliferation by GABA(A) receptor agonists and antagonists, incorporation of thymidine analogues was used. The results showed that the NPE cells express functional extrasynaptic GABA(A) receptors with tonic properties and that low concentration of GABA is required for a baseline level of proliferation. Antagonists of the GABA(A) receptors decreased the proliferation of dissociated E12 NPE cells. Bicuculline also had effects on progenitor cell proliferation in intact E8 and E12 developing retina. The NPE cells had low levels of the Cl-transporter KCC2 compared to the mature retina, suggesting a depolarising role for the GABA(A) receptors. Treatment with KCl, which is known to depolarise membranes, prevented some of the decreased proliferation caused by inhibition of the GABA(A) receptors. This supported the depolarising role for the GABA(A) receptors. Inhibition of L-type voltage-gated Ca2+ channels (VGCCs) reduced the proliferation in the same way as inhibition of the GABA(A) receptors. Inhibition of the channels increased the expression of the cyclin-dependent kinase inhibitor p27(KIP1), along with the reduced proliferation. These results are consistent with that when the membrane potential indirectly regulates cell proliferation with hyperpolarisation of the membrane potential resulting in decreased cell division. The increased expression of p27(KIP1) after inhibition of either the GABA(A) receptors or the L-type VGCCs suggests a link between the GABA(A) receptors, membrane potential, and intracellular Ca2+ in regulating the cell cycle. 

National Category
Physiology
Identifiers
urn:nbn:se:uu:diva-172512 (URN)10.1371/journal.pone.0036874 (DOI)000305336100070 ()
Available from: 2012-04-11 Created: 2012-04-10 Last updated: 2017-12-07Bibliographically approved

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