Adrenaline Stimulates Glucagon Secretion by Tpc2-Dependent Ca2+ Mobilization From Acidic Stores in Pancreatic α-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

43 Citations (SciVal)

Abstract

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+]i in α-cells, which occurred without stimulation of electrical activity and persisted in the absence of extracellular Ca2+ but was sensitive to ryanodine, bafilomycin, and thapsigargin. Adrenaline also increased [Ca2+]i in α-cells in human islets. Genetic or pharmacological inhibition of the 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+]i signaling 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.

Original languageEnglish
Pages (from-to)1128-1139
Number of pages12
JournalDiabetes
Volume67
Issue number6
DOIs
Publication statusPublished - 2018 Jun

Bibliographical note

© 2018 by the American Diabetes Association.

Subject classification (UKÄ)

  • Cell and Molecular Biology

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/metabolism
  • 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

Fingerprint

Dive into the research topics of 'Adrenaline Stimulates Glucagon Secretion by Tpc2-Dependent Ca2+ Mobilization From Acidic Stores in Pancreatic α-Cells'. Together they form a unique fingerprint.

Cite this