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-A;varez, Nicoletta C. Surdo, Manuela Zaccolo, Davide Basco, Paul R.v. Johnson, Reshma Ramracheya, Guy A. Rutter, Antony Galione, Patrik Rorsman, Andrei I. Tarasov

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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 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.
Original languageEnglish
Pages (from-to)1128-1139
Number of pages12
JournalDiabetes
Volume67
Issue number6
Early online date21 Mar 2018
DOIs
Publication statusPublished - 21 May 2018

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    Hamilton, A., Zhang, Q., Salehi, A., Willems, M., Knudsen, J. G., Ringgaard, A. K., Chapman, C. E., Gonzalez-A;varez, A., Surdo, N. C., Zaccolo, M., Basco, D., Johnson, P. R. V., Ramracheya, R., Rutter, G. A., Galione, A., Rorsman, P., & Tarasov, A. I. (2018). Adrenaline Stimulates Glucagon Secretion by Tpc2-Dependent Ca2+ Mobilization From Acidic Stores in Pancreatic α-Cells. Diabetes, 67(6), 1128-1139. https://doi.org/10.2337/db17-1102