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GLP-1 and Exendin-4 Transiently Enhance GABA(A) Receptor-Mediated Synaptic and Tonic Currents in Rat Hippocampal CA3 Pyramidal Neurons
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Fysiologi.ORCID-id: 0000-0001-8279-2790
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Fysiologi.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Fysiologi.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Fysiologi.
2015 (Engelska)Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 64, nr 1, s. 79-89Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

GLP-1 is a hormone that stimulates insulin secretion. Receptors for GLP-1 are also found in the brain, including the hippocampus, the centre for memory and learning. Diabetes mellitus is a risk factor for decreased memory functions. We studied effects of GLP-1 and exendin-4, a GLP-1 receptor agonist, on γ-aminobutyric acid (GABA) signaling in hippocampal CA3 pyramidal neurons. GABA is the main inhibitory neurotransmitter and decreases neuronal excitability. GLP-1 (0.01 – 1 nmol/L) transiently enhanced synaptic and tonic currents and the effects were blocked by exendin(9–39). Ten pmol/L GLP-1 increased both the spontaneous inhibitory postsynaptic current (sIPSC) amplitudes and frequency by a factor of 1.8. In 0.1, 1 nmol/L GLP-1 or 10, 50 or 100 nmol/L exendin-4, only the sIPSC frequency increased. The tonic current was enhanced by 0.01 – 1 nmol/L GLP-1 and by 0.5 – 100 nmol/L exendin-4. When action potentials were inhibited by tetrodotoxin (TTX), IPSCs decreased and currents were no longer potentiated by GLP-1 or exendin-4. In contrast, although the tonic current decreased in TTX, it was still enhanced by GLP-1 or exendin-4. The results demonstrate GLP-1 receptor regulation of hippocampal function and are consistent with GLP-1 receptor agonists enhancing GABAA signaling by pre- and postsynaptic mechanisms.

Ort, förlag, år, upplaga, sidor
2015. Vol. 64, nr 1, s. 79-89
Nationell ämneskategori
Folkhälsovetenskap, global hälsa, socialmedicin och epidemiologi
Identifikatorer
URN: urn:nbn:se:uu:diva-234954DOI: 10.2337/db14-0668ISI: 000346765600010OAI: oai:DiVA.org:uu-234954DiVA, id: diva2:758486
Tillgänglig från: 2014-10-27 Skapad: 2014-10-27 Senast uppdaterad: 2017-12-05Bibliografiskt granskad
Ingår i avhandling
1. GABA signaling regulation by GLP-1 receptor agonists and GABA-A receptors modulator
Öppna denna publikation i ny flik eller fönster >>GABA signaling regulation by GLP-1 receptor agonists and GABA-A receptors modulator
2016 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

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.  

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis, 2016. s. 51
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1209
Nationell ämneskategori
Medicin och hälsovetenskap
Forskningsämne
Neurovetenskap
Identifikatorer
urn:nbn:se:uu:diva-282431 (URN)978-91-554-9548-0 (ISBN)
Disputation
2016-05-31, C2:301, BMC, Husargatan 3, 751 24, Uppsala, 09:15 (Engelska)
Opponent
Handledare
Tillgänglig från: 2016-05-02 Skapad: 2016-04-05 Senast uppdaterad: 2016-05-12

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