| First Author | Hamilton A | Year | 2018 |
| Journal | Diabetes | Volume | 67 |
| Issue | 6 | Pages | 1128-1139 |
| PubMed ID | 29563152 | Mgi Jnum | J:262211 |
| Mgi Id | MGI:6159221 | Doi | 10.2337/db17-1102 |
| Citation | Hamilton A, et al. (2018) Adrenaline Stimulates Glucagon Secretion by Tpc2-Dependent Ca(2+) Mobilization From Acidic Stores in Pancreatic alpha-Cells. Diabetes 67(6):1128-1139 |
| abstractText | Adrenaline is a powerful stimulus of glucagon secretion. It acts by activation of beta-adrenergic receptors, but the downstream mechanisms have only been partially elucidated. Here, we have examined the effects of adrenaline in mouse and human alpha-cells by a combination of electrophysiology, imaging of Ca(2+) 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(2+)]i in alpha-cells, which occurred without stimulation of electrical activity and persisted in the absence of extracellular Ca(2+) but was sensitive to ryanodine, bafilomycin, and thapsigargin. Adrenaline also increased [Ca(2+)]i in alpha-cells in human islets. Genetic or pharmacological inhibition of the Tpc2 channel (that mediates Ca(2+) release from acidic intracellular stores) abolished the stimulatory effect of adrenaline on glucagon secretion and reduced the elevation of [Ca(2+)]i Furthermore, in Tpc2-deficient islets, ryanodine exerted no additive inhibitory effect. These data suggest that beta-adrenergic stimulation of glucagon secretion is controlled by a hierarchy of [Ca(2+)]i signaling in the alpha-cell that is initiated by cAMP-induced Tpc2-dependent Ca(2+) release from the acidic stores and further amplified by Ca(2+)-induced Ca(2+) release from the sarco/endoplasmic reticulum. |
