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- Title
Adrenaline Stimulates Glucagon Secretion by Tpc2-Dependent Ca<sup>2+</sup> Mobilization From Acidic Stores in Pancreatic α-Cells.
- Authors
Hamilton, Alexander; Quan Zhang; 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.; Zhang, Quan
- 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.
- Subjects
CALCIUM metabolism; PROTEIN metabolism; PANCREATIC innervation; ADRENALINE; ANIMAL experimentation; ANIMAL populations; BIOCHEMISTRY; CALCIUM; CELLULAR signal transduction; COMPARATIVE studies; CYTOLOGICAL techniques; CYTOPLASM; ENZYME inhibitors; GLUCAGON; ISLANDS of Langerhans; PHENOMENOLOGY; RESEARCH methodology; MEDICAL cooperation; MEMBRANE proteins; MICE; NEURONS; PANCREAS; PROTEINS; RESEARCH; RESEARCH funding; TISSUE culture; TRANSFERASES; EVALUATION research; CHEMICAL inhibitors; PHARMACODYNAMICS
- Publication
Diabetes, 2018, Vol 67, Issue 6, p1128
- ISSN
0012-1797
- Publication type
journal article
- DOI
10.2337/db17-1102