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Dual effects of muscarinic receptor activation on intracellular ATP in pancreatic ß-cells
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. (Anders Tengholm and Erik Gylfe)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
(English)Manuscript (preprint) (Other academic)
National Category
Cell and Molecular Biology
Research subject
Medical Cell Biology
URN: urn:nbn:se:uu:diva-234963OAI: oai:DiVA.org:uu-234963DiVA: diva2:758504
Available from: 2014-10-27 Created: 2014-10-27 Last updated: 2015-02-03
In thesis
1. ATP Dynamics in Pancreatic α- and β-cells
Open this publication in new window or tab >>ATP Dynamics in Pancreatic α- and β-cells
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Glucose metabolism in pancreatic α- and β-cells is believed to regulate secretion of glucagon and insulin, respectively. In β-cells, ATP links glucose metabolism to electrical activity and insulin secretion. In α-cells, ATP has been attributed various roles in glucose-regulated glucagon release, but the underlying mechanisms are poorly understood. Despite its importance in insulin and glucagon secretion little is known about ATP kinetics in α- and β-cells. In this thesis, the novel fluorescent ATP biosensor Perceval was used to monitor physiologically relevant ATP concentrations with little influence of ADP. Glucose stimulation of β-cells within mouse and human pancreatic islets induced pronounced rise of ATP with superimposed oscillations. Simultaneous measurements of the sub-plasma membrane ATP and Ca2+ concentrations revealed glucose-induced oscillations in opposite phase. ATP increased further and the oscillations ceased when voltage-dependent Ca2+ influx was prevented. In contrast, ATP promptly decreased in response to K+-depolarization-induced elevation of Ca2+. Also mobilization of Ca2+ from intracellular stores lowered ATP, but the negative effect was not due to increased ATP consumption by the sarco/endoplasmic reticulum Ca2+-ATPase. Store-operated Ca2+ entry alone had little effect but markedly elevated ATP when combined with muscarinic receptor activation. When comparing ATP and Ca2+ responses in α- and β-cells within the same islet, glucose-induced ATP generation was much less pronounced and the dose-response relationship left-shifted in the α-cells. At basal glucose, individual α-cells showed Ca2+ and concomitant ATP oscillations in opposite-phase with variable frequency. These oscillations largely cancelled out when averaging data from several α-cells. At high glucose, the Ca2+ and ATP oscillations in α-cells tended to synchronize with the corresponding β-cell oscillations. Since β-cell Ca2+ oscillations drive pulsatile insulin secretion, which is antiparallel to pulsatile glucagon secretion, there seems to be an inverse relationship between changes in α-cell Ca2+ and glucagon release. This paradox is attributed to paracrine inhibition overriding Ca2+ stimulation, since somatostatin receptor blockade potently stimulated glucagon release with little effect on α-cell Ca2+ signalling. The data indicate that complex ATP-Ca2+ interactions in α- and β-cells underlie cell-intrinsic regulation of glucagon and insulin secretion and that paracrine inhibition of glucagon release becomes important in hyperglycaemia.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2014. 53 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1044
ATP, Ca2+, β-cell, α-cell, SERCA, SOCE, muscarinic receptor, insulin secretion, glucagon secretion
National Category
Cell Biology
Research subject
Medical Cell Biology
urn:nbn:se:uu:diva-234345 (URN)978-91-554-9079-9 (ISBN)
Public defence
2014-12-04, B22, Husargatan 3, BMC, Uppsala, 09:15 (English)
Available from: 2014-11-13 Created: 2014-10-16 Last updated: 2015-02-03Bibliographically approved

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