Adrenaline Stimulates Glucagon Secretion by Tpc2-Dependent Ca2+ Mobilization From Acidic Stores in Pancreatic α-Cells
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Adrenaline Stimulates Glucagon Secretion by Tpc2-Dependent Ca2+ Mobilization From Acidic Stores in Pancreatic α-Cells. / Hamilton, Alexander; Zhang, Quan; Salehi, Albert; Willems, Mara; Knudsen, Jakob G.; Ringgaard, Anna K.; Chapman, Caroline E.; Gonzalez-Alvarez, Alejandro; Surdo, Nicoletta C.; Zaccolo, Manuela; Basco, Davide; Johnson, Paul R. V.; Ramracheya, Reshma; Rutter, Guy A.; Galione, Antony; Rorsman, Patrik; Tarasov, Andrei I.
I: Diabetes, Bind 67, Nr. 6, 2018, s. 1128-1139.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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T1 - Adrenaline Stimulates Glucagon Secretion by Tpc2-Dependent Ca2+ Mobilization From Acidic Stores in Pancreatic α-Cells
AU - Hamilton, Alexander
AU - Zhang, Quan
AU - Salehi, Albert
AU - Willems, Mara
AU - Knudsen, Jakob G.
AU - Ringgaard, Anna K.
AU - Chapman, Caroline E.
AU - Gonzalez-Alvarez, Alejandro
AU - Surdo, Nicoletta C.
AU - Zaccolo, Manuela
AU - Basco, Davide
AU - Johnson, Paul R. V.
AU - Ramracheya, Reshma
AU - Rutter, Guy A.
AU - Galione, Antony
AU - Rorsman, Patrik
AU - Tarasov, Andrei I.
PY - 2018
Y1 - 2018
N2 - Adrenaline is a powerful stimulus of glucagon secretion. It acts by activation of b-adrenergic receptors, but the downstream mechanisms have only been partially elucidated. Here, we have examined the effects of adrenaline inmouse and human alpha-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 alpha-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 alpha-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 thatb-adrenergic stimulation of glucagon secretion is controlled by a hierarchy of [Ca2+](i) signaling in the alpha-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.
AB - Adrenaline is a powerful stimulus of glucagon secretion. It acts by activation of b-adrenergic receptors, but the downstream mechanisms have only been partially elucidated. Here, we have examined the effects of adrenaline inmouse and human alpha-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 alpha-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 alpha-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 thatb-adrenergic stimulation of glucagon secretion is controlled by a hierarchy of [Ca2+](i) signaling in the alpha-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.
U2 - 10.2337/db17-1102
DO - 10.2337/db17-1102
M3 - Journal article
C2 - 29563152
VL - 67
SP - 1128
EP - 1139
JO - Diabetes
JF - Diabetes
SN - 0012-1797
IS - 6
ER -
ID: 213158265