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In Intact Islets Interstitial GABA Activates GABA(A) Receptors That Generate Tonic Currents in alpha-Cells
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.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.ORCID-id: 0000-0003-4661-5724
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2013 (Engelska)Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, nr 6, s. e67228-Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

In the rat islets γ-aminobutyric acid (GABA) is produced by the β-cells and, at least, the α-cells express the GABAA receptors (GABAA channels). In this study, we examined in intact islets if the interstitial GABA activated the GABAA receptors. We used the patch-clamp technique to record whole-cell and single-channel currents and single-cell RT-PCR to identify the cell-type we recorded from, in the intact rat islets. We further identified which GABAA receptor subunits were expressed. We determined the cell-type of 43 cells we recorded from and of these 49%, 28% and 7% were α, β and δ-cells, respectively. In the remaining 16% of the cells, mRNA transcripts of more than one hormone gene were detected. The results show that in rat islets interstitial GABA activates tonic current in the α-cells but not in the β-cells. Seventeen different GABAA receptor subunits are expressed with high expression of α1, α2, α4, α6, β3, γ1, δ, ρ1, ρ2 and ρ3 subunits whereas no expression was detected for α5 or ε subunits. The abundance of the GABAA receptor subunits detected suggests that a number of GABAA receptor subtypes are formed in the islets. The single-channel and tonic currents were enhanced by pentobarbital and inhibited by the GABAA receptor antagonist SR-95531. The single-channel conductance ranged from 24 to 105 pS. Whether the single-channel conductance is related to subtypes of the GABAA receptor or variable interstitial GABA concentrations remains to be determined. Our results reveal that GABA is an extracellular signaling molecule in rat pancreatic islets and reaches concentration levels that activate GABAA receptors on the glucagon-releasing α-cells.

Ort, förlag, år, upplaga, sidor
2013. Vol. 8, nr 6, s. e67228-
Nationell ämneskategori
Fysiologi
Identifikatorer
URN: urn:nbn:se:uu:diva-203228DOI: 10.1371/journal.pone.0067228ISI: 000321738400122PubMedID: 23826240OAI: oai:DiVA.org:uu-203228DiVA, id: diva2:635776
Tillgänglig från: 2013-07-05 Skapad: 2013-07-05 Senast uppdaterad: 2019-02-01Bibliografiskt granskad
Ingår i avhandling
1. The Cross-Talk between GABA Signalling and Metabolic Hormones in the Brain and Pancreatic Islets
Öppna denna publikation i ny flik eller fönster >>The Cross-Talk between GABA Signalling and Metabolic Hormones in the Brain and Pancreatic Islets
2013 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

GABA is a well-known neurotransmitter that can be synthesized in the central nervous system (CNS) and, interestingly, also in pancreatic islets. Once released, GABA activates GABA-A channels tonically or transiently resulting in different physiological functions. The pancreatic islets are important micro-organs composed of mainly α, β and δ cells secreting the metabolic hormones, namely insulin, glucagon and somatosatin, respectively. When insulin is secreted from pancreatic β cells, it can enter the blood and travel to the target tissues including the brain where the insulin receptor is prominently expressed such as in the hippocampus. It has been suggested that insulin regulates hippocampal function and, thereby, possibly modulates cognition. However, how this comes about is not understood. On the other hand, GABA secreted from the pancreatic β cells can regulate the islet cells via the para or autocrine loop. Nevertheless, in order to elucidate the details of GABA effects on cellular function, more insight into the pharmacological characteristics of GABA-A receptors, the physiological concentration of GABA and activation types of the GABA-receptors are required. We, therefore, used the whole-cell and single-channel patch-clamp technique to record from cells in the hippocampal slice and pancreatic islets for studying the function of GABA-A receptors and how they are modified by hormones, GABA or drugs. RT-qPCR was utilized to profile the expression of GABA-A receptors in the intact tissues. We also initiated the patch-clamp combined single-cell RT-PCR in the intact rat and human islets to investigate the cell-specific function of GABA-A receptors.

We have shown in acute rat hippocampal slices that 1 nM insulin “turns on” extrasynaptic GABA-A receptors in CA1 pyramidal neurons resulting in decreased frequency of action potential firing. The single-channel current amplitude is related to the GABA concentration resulting in a single-channel GABA affinity in the pM range. The benzodiazepines, flumazenil and zolpidem, are inverse agonists. The results demonstrated an unexpected hormonal control of the inhibitory channel subtype expressed and excitability of hippocampal neurons.

In the intact rat islets, the GABA-evoked tonic currents were present in the α cells and may contribute to keeping the resting membrane potential of α cells population at hyperpolarized membrane potential and, thereby, making it more difficult to depolarize the cells. In the human, the GABA signaling system was compromised in islets from type 2 diabetic individuals, where the expression of genes encoding the α1, α2, β2 and β3 GABA-A receptor subunits were down-regulated. GABA originating within the islets evoked tonic currents in the α, β and δ cells. However, transient current was observed only in δ cells, which implies a rapid regulation of somatostatin secretion by GABA. The effects of SR95531 on hormone release revealed that activation of GABA-A receptors decreased both insulin and glucagon secretion. The data is important for understanding the mechanism underlying GABA regulation of hormones secretion in human islets.

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis, 2013. s. 40
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 947
Nationell ämneskategori
Medicin och hälsovetenskap
Identifikatorer
urn:nbn:se:uu:diva-209532 (URN)978-91-554-8795-9 (ISBN)
Disputation
2013-12-12, lecture hall A1:111a, BMC, Husargatan 3, Uppsala, 13:15 (Engelska)
Opponent
Handledare
Tillgänglig från: 2013-11-21 Skapad: 2013-10-21 Senast uppdaterad: 2014-01-23

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