Adrenaline stimulates glucagon secretion by Tpc2-dependent Ca2+ mobilization from acidic stores in pancreatic α-cells

Journal article

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.

Authors: Hamilton, A; Zhang, Q; Salehi, A; Willems, M; Knudsen, JG

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: American Diabetes Association
• Journal: Diabetes
• Volume: 67
• Issue: 6
• Pages: 1128-1139
• Publication date: 2018-03-21
• Acceptance date: 2018-03-13
• DOI: 10.2337/db17-1102
• EISSN: 1939-327X
• ISSN: 0012-1797
• Pmid: 29563152
• Language: English
• Keywords: glucagon; adrenaline; pancreatic α-cells; two-pore channels