uu.seUppsala University Publications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
In a cell-type specific manner, high-affinity GABA-A receptors participate in autocrine and paracrine GABA signaling in human pancreatic islets
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
University of Newcastle.
Show others and affiliations
(English)Manuscript (preprint) (Other academic)
Abstract [en]

γ-Aminobutyric acid (GABA), best known as the classical inhibitory neurotransmitter, is also produced and released by pancreatic islet cells. The hormone secreting α, β and δ- cells in human islets express GABA-A receptors that are activated by GABA. GABA signaling in the islets is thought to regulate hormone secretion but how it comes about is unclear. To-date the interstitial GABA concentration and cell-type specific GABA-A receptors have not been characterized. As a consequence, it is not clear how the interstitial GABA in the intact human islet regulates the specific cell-types. We have set- up single-cell RT-PCR combined whole-cell patch-clamp to investigate the functional role of GABA-A receptors in identified cell within intact human islets. GABA-activated tonic current is present in all α, β and δ-cells whereas only the δ-cells respond to GABA with large, transient currents. High-affinity GABA-A receptors activated with interstitial concentrations lower than 10 nM GABA are expressed in both α and β-cells. In the β- cells different subtypes of GABA-A receptors were identified based on single-channel kinetics, current-voltage relation and pharmacology. The data provides insight into the mechanisms underlying GABA regulation of different cell-types in intact human islet.

National Category
Medical and Health Sciences
Research subject
Physiology
Identifiers
URN: urn:nbn:se:uu:diva-209530OAI: oai:DiVA.org:uu-209530DiVA: diva2:658346
Available from: 2013-10-21 Created: 2013-10-21 Last updated: 2013-11-22Bibliographically approved
In thesis
1. The Cross-Talk between GABA Signalling and Metabolic Hormones in the Brain and Pancreatic Islets
Open this publication in new window or tab >>The Cross-Talk between GABA Signalling and Metabolic Hormones in the Brain and Pancreatic Islets
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
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.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2013. 40 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 947
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-209532 (URN)978-91-554-8795-9 (ISBN)
Public defence
2013-12-12, lecture hall A1:111a, BMC, Husargatan 3, Uppsala, 13:15 (English)
Opponent
Supervisors
Available from: 2013-11-21 Created: 2013-10-21 Last updated: 2014-01-23

Open Access in DiVA

No full text

Authority records BETA

Jin, YangKorol, SergiyJin, ZheBirnir, Bryndis

Search in DiVA

By author/editor
Jin, YangKorol, SergiyJin, ZheBirnir, Bryndis
By organisation
Physiology
Medical and Health Sciences

Search outside of DiVA

GoogleGoogle Scholar

urn-nbn

Altmetric score

urn-nbn
Total: 687 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf