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Adrenaline Stimulates Glucagon Secretion by Tpc2-Dependent Ca2+ Mobilization From Acidic Stores in Pancreatic α-Cells

Hamilton, Alexander LU ; Zhang, Quan ; Salehi, Albert LU orcid ; Willems, Mara ; Knudsen, Jakob G ; Ringgaard, Anna K ; Chapman, Caroline E ; Gonzalez-Alvarez, Alejandro ; Surdo, Nicoletta C and Zaccolo, Manuela , et al. (2018) In Diabetes 67(6). p.1128-1139
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 and persisted in the absence of extracellular Ca2+ but was sensitive to ryanodine, bafilomycin, and thapsigargin. Adrenaline also increased [Ca2+]i in α-cells in... (More)

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 and 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 the 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.

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type
Contribution to journal
publication status
published
subject
keywords
Adrenergic Neurons/cytology, Animals, Animals, Outbred Strains, Calcium Channels/chemistry, Calcium Signaling/drug effects, Cyclic AMP-Dependent Protein Kinases/antagonists & inhibitors, Endoplasmic Reticulum/drug effects, Enzyme Inhibitors/pharmacology, Epinephrine/metabolism, Glucagon/metabolism, Glucagon-Secreting Cells/cytology, Guanine Nucleotide Exchange Factors/antagonists & inhibitors, Humans, Membrane Transport Modulators/pharmacology, Mice, Mice, Inbred C57BL, Mice, Knockout, Pancreas/drug effects, Patch-Clamp Techniques, Sarcoplasmic Reticulum/drug effects, Tissue Culture Techniques, Up-Regulation/drug effects
in
Diabetes
volume
67
issue
6
pages
12 pages
publisher
American Diabetes Association Inc.
external identifiers
  • pmid:29563152
  • scopus:85047739348
ISSN
1939-327X
DOI
10.2337/db17-1102
language
English
LU publication?
no
additional info
© 2018 by the American Diabetes Association.
id
fbe9da0f-6044-4a8b-a289-7624ef5fb96f
date added to LUP
2019-05-22 16:56:00
date last changed
2022-05-23 06:26:50
@article{fbe9da0f-6044-4a8b-a289-7624ef5fb96f,
  abstract     = {{<p>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 and 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 the 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.</p>}},
  author       = {{Hamilton, Alexander and Zhang, Quan and Salehi, Albert and Willems, Mara and Knudsen, Jakob G and Ringgaard, Anna K and Chapman, Caroline E and Gonzalez-Alvarez, Alejandro and Surdo, Nicoletta C and Zaccolo, Manuela and Basco, Davide and Johnson, Paul R V and Ramracheya, Reshma and Rutter, Guy A and Galione, Antony and Rorsman, Patrik and Tarasov, Andrei I}},
  issn         = {{1939-327X}},
  keywords     = {{Adrenergic Neurons/cytology; Animals; Animals, Outbred Strains; Calcium Channels/chemistry; Calcium Signaling/drug effects; Cyclic AMP-Dependent Protein Kinases/antagonists & inhibitors; Endoplasmic Reticulum/drug effects; Enzyme Inhibitors/pharmacology; Epinephrine/metabolism; Glucagon/metabolism; Glucagon-Secreting Cells/cytology; Guanine Nucleotide Exchange Factors/antagonists & inhibitors; Humans; Membrane Transport Modulators/pharmacology; Mice; Mice, Inbred C57BL; Mice, Knockout; Pancreas/drug effects; Patch-Clamp Techniques; Sarcoplasmic Reticulum/drug effects; Tissue Culture Techniques; Up-Regulation/drug effects}},
  language     = {{eng}},
  number       = {{6}},
  pages        = {{1128--1139}},
  publisher    = {{American Diabetes Association Inc.}},
  series       = {{Diabetes}},
  title        = {{Adrenaline Stimulates Glucagon Secretion by Tpc2-Dependent Ca2+ Mobilization From Acidic Stores in Pancreatic α-Cells}},
  url          = {{http://dx.doi.org/10.2337/db17-1102}},
  doi          = {{10.2337/db17-1102}},
  volume       = {{67}},
  year         = {{2018}},
}