University of Hertfordshire

From the same journal

By the same 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
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Original languageEnglish
Number of pages12
Pages (from-to)1128-1139
JournalDiabetes
Journal publication date1 Jun 2018
Volume67
Issue6
Early online date21 May 2018
DOIs
Publication statusPublished - 1 Jun 2018

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.

ID: 15266400