GABA signaling regulation by GLP-1 receptor agonists and GABA-A receptors modulator
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 a...
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Uppsala universitet, Fysiologi
2016
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ndltd-UPSALLA1-oai-DiVA.org-uu-2824312016-05-13T05:20:02ZGABA signaling regulation by GLP-1 receptor agonists and GABA-A receptors modulatorengBabateen, Omar M.Uppsala universitet, FysiologiUppsala2016GABA (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. Doctoral thesis, comprehensive summaryinfo:eu-repo/semantics/doctoralThesistexthttp://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-282431urn:isbn:978-91-554-9548-0Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, 1651-6206 ; 1209application/pdfinfo:eu-repo/semantics/openAccess |
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language |
English |
format |
Doctoral Thesis |
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NDLTD |
description |
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. |
author |
Babateen, Omar M. |
spellingShingle |
Babateen, Omar M. GABA signaling regulation by GLP-1 receptor agonists and GABA-A receptors modulator |
author_facet |
Babateen, Omar M. |
author_sort |
Babateen, Omar M. |
title |
GABA signaling regulation by GLP-1 receptor agonists and GABA-A receptors modulator |
title_short |
GABA signaling regulation by GLP-1 receptor agonists and GABA-A receptors modulator |
title_full |
GABA signaling regulation by GLP-1 receptor agonists and GABA-A receptors modulator |
title_fullStr |
GABA signaling regulation by GLP-1 receptor agonists and GABA-A receptors modulator |
title_full_unstemmed |
GABA signaling regulation by GLP-1 receptor agonists and GABA-A receptors modulator |
title_sort |
gaba signaling regulation by glp-1 receptor agonists and gaba-a receptors modulator |
publisher |
Uppsala universitet, Fysiologi |
publishDate |
2016 |
url |
http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-282431 http://nbn-resolving.de/urn:isbn:978-91-554-9548-0 |
work_keys_str_mv |
AT babateenomarm gabasignalingregulationbyglp1receptoragonistsandgabaareceptorsmodulator |
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1718268488504573952 |