Abstract
Adrenaline is a powerful stimulus of glucagon secretion. It acts by activation of b-adrenergic receptors, but the downstream mechanisms have only been partially elucidated. Here, we have examined the effects of adrenaline in mouse and human a-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 a-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 a-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 b-adrenergic stimulation of glucagon secretion is controlled by a hierarchy of [Ca 2+] i signaling in the a-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.
Original language | English |
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Pages (from-to) | 1128-1139 |
Number of pages | 12 |
Journal | Diabetes |
Volume | 67 |
Issue number | 6 |
Early online date | 21 May 2018 |
DOIs | |
Publication status | Published - 1 Jun 2018 |
Keywords
- Adrenergic Neurons/cytology
- Animals
- Animals, Outbred Strains
- Calcium Channels/chemistry
- Calcium Signaling/drug effects
- Cyclic AMP-Dependent Protein Kinases/antagonists & inhibitors
- Endoplasmic Reticulum/drug effects
- Enzyme Inhibitors/pharmacology
- Epinephrine/metabolism
- Glucagon/secretion
- Glucagon-Secreting Cells/cytology
- Guanine Nucleotide Exchange Factors/antagonists & inhibitors
- Humans
- Membrane Transport Modulators/pharmacology
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Pancreas/drug effects
- Patch-Clamp Techniques
- Sarcoplasmic Reticulum/drug effects
- Tissue Culture Techniques
- Up-Regulation/drug effects