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 Ca 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 [Ca] in α-cells, which occurred without stimulation of electrical activity and persisted in the absence of extracellular Ca but was sensitive to ryanodine, bafilomycin, and thapsigargin. Adrenaline also increased [Ca] in α-cells in human islets. Genetic or pharmacological inhibition of the Tpc2 channel (that mediates Ca release from acidic intracellular stores) abolished the stimulatory effect of adrenaline on glucagon secretion and reduced the elevation of [Ca] 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 [Ca] signaling in the α-cell that is initiated by cAMP-induced Tpc2-dependent Ca release from the acidic stores and further amplified by Ca-induced Ca release from the sarco/endoplasmic reticulum.
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| http://dx.doi.org/10.2337/db17-1102 | DOI Listing |
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