The endoplasmic reticulum plays a key role in α-cell intracellular Ca2+ dynamics and glucose-regulated glucagon secretion in mouse islets

Samuel Acreman, Jinfang Ma, Geoffrey Denwood, Rui Gao, Andrei Tarasov, Patrik Rorsman, Quan Zhang

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Abstract

Glucagon is secreted by pancreatic α-cells to counteract hypoglycaemia. How glucose regulates glucagon secretion remains unclear. Here, using mouse islets, we studied the role of transmembrane and endoplasmic reticulum (ER) Ca2+ on intrinsic α-cell glucagon secretion. Blocking isradipine-sensitive L-type voltage-gated Ca2+ (Cav) channels abolished α-cell electrical activity but had little impact on its cytosolic Ca2+ oscillations or low-glucose-stimulated glucagon secretion. In contrast, depleting ER Ca2+ with cyclopiazonic acid or blocking ER Ca2+-releasing ryanodine receptors abolished α-cell glucose sensitivity and low-glucose-stimulated glucagon secretion. ER Ca2+ mobilization in α-cells is regulated by intracellular ATP and likely to be coupled to Ca2+ influx through P/Q-type Cav channels. ω-Agatoxin IVA blocked α-cell ER Ca2+ release and cell exocytosis, but had no additive effect on glucagon secretion when combined with ryanodine. We conclude that glucose regulates glucagon secretion through the control of ER Ca2+ mobilization, a mechanism that can be independent of α-cell electrical activity.
Original languageEnglish
Article number109665
Pages (from-to)1-19
Number of pages19
JournaliScience
Volume27
Issue number5
Early online date5 Apr 2024
DOIs
Publication statusPublished (in print/issue) - 17 May 2024

Bibliographical note

Publisher Copyright:
© 2024 The Author(s)

Keywords

  • Cell biology
  • Cellular physiology
  • Physiology

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