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

Research output: Contribution to journalArticle

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.

Details

Authors
  • 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
External organisations
  • University of Oxford
  • University of Gothenburg
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • 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
Original languageEnglish
Pages (from-to)1128-1139
Number of pages12
JournalDiabetes
Volume67
Issue number6
Publication statusPublished - 2018 Jun
Publication categoryResearch
Peer-reviewedYes
Externally publishedYes

Bibliographic note

© 2018 by the American Diabetes Association.