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Adrenaline stimulates glucagon secretion by Tpc2-dependent Ca2+ mobilization from acidic stores in pancreatic α-Cells

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Title: Adrenaline stimulates glucagon secretion by Tpc2-dependent Ca2+ mobilization from acidic stores in pancreatic α-Cells
Authors: Hamilton, A
Zhang, Q
Salehi, A
Willems, M
Knudsen, JG
Ringgaard, AK
Chapman, CE
Gonzalez-Alvarez, A
Surdo, NC
Zaccolo, M
Basco, D
Johnson, PRV
Ramracheya, R
Rutter, GA
Galione, A
Rorsman, P
Tarasov, AI
Item Type: Journal Article
Abstract: Adrenaline is a powerful stimulus of glucagon secretion. It acts by activation of β-adrenergic receptors but the downstream mechanisms have only been partially elucidated. Here we have examined the effects of adrenaline in mouse and human α-cells by a combination of electrophysiology, imaging of Ca2+ and PKA activity and hormone release measurements. We found that stimulation of glucagon secretion correlated with a PKA- and EPAC2-dependent (inhibited by PKI and ESI-05, respectively) elevation of [Ca2+]i in α-cells, which occurred without stimulation of electrical activity, persisted in the absence of extracellular Ca2+ but was sensitive to ryanodine, bafilomycin and thapsigargin. Adrenaline also increased [Ca2+]i in α-cells in human islets. Genetic or pharmacological inhibition of Tpc2 channel (that mediates Ca2+ release from acidic intracellular stores) abolished the stimulatory effect of adrenaline on glucagon secretion and reduced the elevation of [Ca2+]i. Furthermore, in Tpc2-deficient islets, ryanodine exerted no additive inhibitory effect. These data suggest that β-adrenergic stimulation of glucagon secretion is controlled by a hierarchy of [Ca2+]i signaling in the α-cell that is initiated by cAMP-induced Tpc2-dependent Ca2+ release from the acidic stores and further amplified by Ca2+-induced Ca2+ release from the sarco/endoplasmic reticulum.
Issue Date: 1-Jun-2018
Date of Acceptance: 13-Mar-2018
URI: http://hdl.handle.net/10044/1/58398
DOI: https://dx.doi.org/10.2337/db17-1102
ISSN: 0012-1797
Publisher: American Diabetes Association
Start Page: 1128
End Page: 1139
Journal / Book Title: Diabetes
Volume: 67
Issue: 6
Copyright Statement: © 2018 by the American Diabetes Association. http://www.diabetesjournals.org/content/licenseReaders may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals.org/content/license.
Keywords: Science & Technology
Life Sciences & Biomedicine
Endocrinology & Metabolism
2-PORE CHANNELS
ENDOCRINE PANCREAS
INSULIN-SECRETION
DELTA CELLS
BETA-CELLS
NAADP
MOUSE
CALCIUM
GLUCOSE
ISLETS
Adrenergic Neurons
Animals
Animals, Outbred Strains
Calcium Channels
Calcium Signaling
Cyclic AMP-Dependent Protein Kinases
Endoplasmic Reticulum
Enzyme Inhibitors
Epinephrine
Glucagon
Glucagon-Secreting Cells
Guanine Nucleotide Exchange Factors
Humans
Membrane Transport Modulators
Mice
Mice, Inbred C57BL
Mice, Knockout
Pancreas
Patch-Clamp Techniques
Sarcoplasmic Reticulum
Tissue Culture Techniques
Up-Regulation
11 Medical And Health Sciences
Publication Status: Published
Conference Place: United States
Online Publication Date: 2018-03-21
Appears in Collections:Department of Medicine
Faculty of Medicine



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