Adrenaline Stimulates Glucagon Secretion by Tpc2-Dependent Ca2+Mobilization from Acidic Stores in Pancreatic α-Cells.
Hamilton A., Zhang Q., Salehi A., Willems M., Knudsen JG., Ringgaard AK., Chapman CE., Gonzalez-Alvarez A., Surdo NC., Zaccolo M., Basco D., Johnson PRV., Ramracheya R., Rutter GA., Galione A., Rorsman P., Tarasov AI.
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+]iin 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+]iin 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+]isignaling 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.