GABA signaling regulation by GLP-1 receptor agonists and GABA-A receptors modulator
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
GABA (γ-aminobutyric acid) is the main neuroinhibitory transmitter in mammalian brains. It binds to GABA-A and GABA-B receptors. The GABA-A receptors are ligand-gated chloride channels. A variety of GABA-A receptor agonists and antagonists have been developed to study the GABA-mediated inhibition and to explore new medications. In this thesis I have examined the role of GABA in brain tumors and the effects of the metabolic hormone GLP-1 on GABAergic signaling in neurons.
I studied if GABA-A receptors subunits were expressed and formed functional ion channels in the glioblastoma cell line U3047MG. I identified the mRNA of 11, α2, α3, α5, β1, β2, β3, δ, γ3, π, θ and ρ2, out of the 19 known GABA-A subunits. Immunostaining demonstrated abundant expression of the α3 and β3 subunits. Interestingly, whole-cell GABA-activated currents were recorded in only 12% of the cells. The GABA-activated currents half-maximal concentration (EC50) was 36 µM. The currents were modulated by diazepam (1 µM) and the general anesthetics propofol (50 µM) and etomidate (EC50 = 50 nM).
GLP-1 and exendin-4 transiently enhanced the GABA-A receptor-mediated currents in CA3 neurons of the rat hippocampus. The tonic and the spontaneous inhibitory postsynaptic currents increased as compared to control in a concentration dependent manner. The increase was related to enhanced release of GABA from the presynaptic terminals and increased insertion or affinity of GABA-A receptors in the CA3 postsynaptic neuron. In contrast to GLP-1 and exendin-4, liraglutide enhanced the currents only in a subset of the neurons and the effect was mainly mediated by presynaptic mechanisms.
In conclusion, GABA signaling in neurons is modified by the metabolic hormone GLP-1 and its mimetics highlighting the important cross-talk that takes place between the brain and other organs. Medicines modifying GABA signaling in the brain may be important for a number of diseases.
Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2016. , 51 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1209
Medical and Health Sciences
Research subject Neuroscience
IdentifiersURN: urn:nbn:se:uu:diva-282431ISBN: 978-91-554-9548-0OAI: oai:DiVA.org:uu-282431DiVA: diva2:917455
2016-05-31, C2:301, BMC, Husargatan 3, 751 24, Uppsala, 09:15 (English)
Eliasson, Lena, Professor
Birnir, Bryndis, Professor
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