TY - JOUR
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-A;varez, 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 - 2018/5/21
Y1 - 2018/5/21
N2 - 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.
AB - 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.
UR - http://diabetes.diabetesjournals.org/lookup/doi/10.2337/db17-1102
UR - https://www.ncbi.nlm.nih.gov/pubmed/29563152
UR - https://pure.ulster.ac.uk/en/publications/adrenaline-stimulates-glucagon-secretion-by-tpc2-dependent-ca2-mo
U2 - 10.2337/db17-1102
DO - 10.2337/db17-1102
M3 - Article
SN - 0012-1797
VL - 67
SP - 1128
EP - 1139
JO - Diabetes
JF - Diabetes
IS - 6
ER -