Adrenaline stimulates glucagon secretion by Tpc2-Dependent ca 2+ mobilization from acidic stores in pancreatic a-Cells

Alexander Hamilton, Quan Zhang, Albert Salehi, Mara Willems, Jakob G Knudsen, Anna K Ringgaard, Caroline E Chapman, Alejandro Gonzalez-Alvarez, Nicoletta C Surdo, Manuela Zaccolo, Davide Basco, Paul R V Johnson, Reshma Ramracheya, Guy A Rutter, Antony Galione, Patrik Rorsman, Andrei I Tarasov

Research output: Contribution to journalArticlepeer-review

30 Citations (Scopus)


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 languageEnglish
Pages (from-to)1128-1139
Number of pages12
Issue number6
Early online date21 May 2018
Publication statusPublished - 1 Jun 2018


  • 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


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