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Original Research
Adrenaline Stimulates Glucagon Secretion by Tpc2-Dependent Ca2+ Mobilization from Acidic Stores in Pancreatic α-Cells
Alexander Hamilton, Quan Zhang, Albert Salehi, Mara Willems, Jakob G. Knudsen, Anna K. Ringgaard, Caroline E. Chapman, Alejandro Gonzalez-Alvarez, Nicoletta C. Surdo, Manuela Zaccolo, Davide Basco, Paul R.V. Johnson, Reshma Ramracheya, Guy A. Rutter, Antony Galione, Patrik Rorsman and Andrei I. Tarasov
Diabetes 2018 Mar; db171102. https://doi.org/10.2337/db17-1102
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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.

Footnotes

  • This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db17-1102.

  • Received September 15, 2017.
  • Accepted March 13, 2018.
  • © 2018 by the American Diabetes Association.
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Adrenaline Stimulates Glucagon Secretion by Tpc2-Dependent Ca2+ Mobilization from Acidic Stores in Pancreatic α-Cells
Alexander Hamilton, Quan Zhang, Albert Salehi, Mara Willems, Jakob G. Knudsen, Anna K. Ringgaard, Caroline E. Chapman, Alejandro Gonzalez-Alvarez, Nicoletta C. Surdo, Manuela Zaccolo, Davide Basco, Paul R.V. Johnson, Reshma Ramracheya, Guy A. Rutter, Antony Galione, Patrik Rorsman, Andrei I. Tarasov
Diabetes Mar 2018, db171102; DOI: 10.2337/db17-1102

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Adrenaline Stimulates Glucagon Secretion by Tpc2-Dependent Ca2+ Mobilization from Acidic Stores in Pancreatic α-Cells
Alexander Hamilton, Quan Zhang, Albert Salehi, Mara Willems, Jakob G. Knudsen, Anna K. Ringgaard, Caroline E. Chapman, Alejandro Gonzalez-Alvarez, Nicoletta C. Surdo, Manuela Zaccolo, Davide Basco, Paul R.V. Johnson, Reshma Ramracheya, Guy A. Rutter, Antony Galione, Patrik Rorsman, Andrei I. Tarasov
Diabetes Mar 2018, db171102; DOI: 10.2337/db17-1102
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