GABA signaling regulation by GLP-1 receptor agonists and GABA-A receptors modulator

Babateen, O. M. 2016. GABA signaling regulation by GLP-1 receptor agonists and GABAA receptors modulator. Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine 1209. 51 pp. Uppsala: Acta Universitatis Upsaliensis. ISBN 978-91-554-9548-0. 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. Omar M. Babateen, Department of Neuroscience, Physiology, Box 593, Uppsala University, SE-75123 Uppsala, Sweden. © Omar M. Babateen 2016 ISSN 1651-6206 ISBN 978-91-554-9548-0 urn:nbn:se:uu:diva-282431 (http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-282431) انيضام يف اھرضاحو اھعبنم برغلا مولع انيضارا يف نكستل اھلـــقننل انبرـــــغت