Functional Characterization of Native, High-Affinity GABAA Receptors in Human Pancreatic β Cells
In human pancreatic islets, the neurotransmitter γ-aminobutyric acid (GABA) is an extracellular signaling molecule synthesized by and released from the insulin-secreting β cells. The effective, physiological GABA concentration range within human islets is unknown. Here we use native GABAA receptors...
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doaj-1bc71a74c5a548beb4885579c89914562020-11-25T01:32:03ZengElsevierEBioMedicine2352-39642018-04-0130273282Functional Characterization of Native, High-Affinity GABAA Receptors in Human Pancreatic β CellsSergiy V. Korol0Zhe Jin1Yang Jin2Amol K. Bhandage3Anders Tengholm4Nikhil R. Gandasi5Sebastian Barg6Daniel Espes7Per-Ola Carlsson8Derek Laver9Bryndis Birnir10Department of Neuroscience, Uppsala University, 75124 Uppsala, SwedenDepartment of Neuroscience, Uppsala University, 75124 Uppsala, SwedenDepartment of Neuroscience, Uppsala University, 75124 Uppsala, SwedenDepartment of Neuroscience, Uppsala University, 75124 Uppsala, SwedenDepartment of Medical Cell Biology, Uppsala University, 75124 Uppsala, SwedenDepartment of Neuroscience, Uppsala University, 75124 Uppsala, Sweden; Department of Medical Cell Biology, Uppsala University, 75124 Uppsala, SwedenDepartment of Medical Cell Biology, Uppsala University, 75124 Uppsala, SwedenDepartment of Medical Cell Biology, Uppsala University, 75124 Uppsala, SwedenDepartment of Medical Cell Biology, Uppsala University, 75124 Uppsala, SwedenSchool of Biomedical Sciences and Pharmacy, University of Newcastle, Hunter Medical Research Institute, Callaghan, NSW 2308, AustraliaDepartment of Neuroscience, Uppsala University, 75124 Uppsala, Sweden; Corresponding author.In human pancreatic islets, the neurotransmitter γ-aminobutyric acid (GABA) is an extracellular signaling molecule synthesized by and released from the insulin-secreting β cells. The effective, physiological GABA concentration range within human islets is unknown. Here we use native GABAA receptors in human islet β cells as biological sensors and reveal that 100–1000 nM GABA elicit the maximal opening frequency of the single-channels. In saturating GABA, the channels desensitized and stopped working. GABA modulated insulin exocytosis and glucose-stimulated insulin secretion. GABAA receptor currents were enhanced by the benzodiazepine diazepam, the anesthetic propofol and the incretin glucagon-like peptide-1 (GLP-1) but not affected by the hypnotic zolpidem. In type 2 diabetes (T2D) islets, single-channel analysis revealed higher GABA affinity of the receptors. The findings reveal unique GABAA receptors signaling in human islets β cells that is GABA concentration-dependent, differentially regulated by drugs, modulates insulin secretion and is altered in T2D. Keywords: GABA, GABAA receptor, Pancreatic islet, Type 2 diabeteshttp://www.sciencedirect.com/science/article/pii/S2352396418300987 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Sergiy V. Korol Zhe Jin Yang Jin Amol K. Bhandage Anders Tengholm Nikhil R. Gandasi Sebastian Barg Daniel Espes Per-Ola Carlsson Derek Laver Bryndis Birnir |
spellingShingle |
Sergiy V. Korol Zhe Jin Yang Jin Amol K. Bhandage Anders Tengholm Nikhil R. Gandasi Sebastian Barg Daniel Espes Per-Ola Carlsson Derek Laver Bryndis Birnir Functional Characterization of Native, High-Affinity GABAA Receptors in Human Pancreatic β Cells EBioMedicine |
author_facet |
Sergiy V. Korol Zhe Jin Yang Jin Amol K. Bhandage Anders Tengholm Nikhil R. Gandasi Sebastian Barg Daniel Espes Per-Ola Carlsson Derek Laver Bryndis Birnir |
author_sort |
Sergiy V. Korol |
title |
Functional Characterization of Native, High-Affinity GABAA Receptors in Human Pancreatic β Cells |
title_short |
Functional Characterization of Native, High-Affinity GABAA Receptors in Human Pancreatic β Cells |
title_full |
Functional Characterization of Native, High-Affinity GABAA Receptors in Human Pancreatic β Cells |
title_fullStr |
Functional Characterization of Native, High-Affinity GABAA Receptors in Human Pancreatic β Cells |
title_full_unstemmed |
Functional Characterization of Native, High-Affinity GABAA Receptors in Human Pancreatic β Cells |
title_sort |
functional characterization of native, high-affinity gabaa receptors in human pancreatic β cells |
publisher |
Elsevier |
series |
EBioMedicine |
issn |
2352-3964 |
publishDate |
2018-04-01 |
description |
In human pancreatic islets, the neurotransmitter γ-aminobutyric acid (GABA) is an extracellular signaling molecule synthesized by and released from the insulin-secreting β cells. The effective, physiological GABA concentration range within human islets is unknown. Here we use native GABAA receptors in human islet β cells as biological sensors and reveal that 100–1000 nM GABA elicit the maximal opening frequency of the single-channels. In saturating GABA, the channels desensitized and stopped working. GABA modulated insulin exocytosis and glucose-stimulated insulin secretion. GABAA receptor currents were enhanced by the benzodiazepine diazepam, the anesthetic propofol and the incretin glucagon-like peptide-1 (GLP-1) but not affected by the hypnotic zolpidem. In type 2 diabetes (T2D) islets, single-channel analysis revealed higher GABA affinity of the receptors. The findings reveal unique GABAA receptors signaling in human islets β cells that is GABA concentration-dependent, differentially regulated by drugs, modulates insulin secretion and is altered in T2D. Keywords: GABA, GABAA receptor, Pancreatic islet, Type 2 diabetes |
url |
http://www.sciencedirect.com/science/article/pii/S2352396418300987 |
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