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

iScience (May 2024)

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

Affiliations

Samuel Acreman: Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 7LE, UK; Institute of Neuroscience and Physiology, Department of Physiology, Metabolic Research Unit, Sahlgrenska Academy, University of Gothenburg, Box 430, S-405 30 Gothenburg, Sweden
Jinfang Ma: Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 7LE, UK; Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu, China
Geoffrey Denwood: Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 7LE, UK
Rui Gao: Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 7LE, UK
Andrei Tarasov: Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 7LE, UK; Biomedical Sciences Research Institute, School of Biomedical Sciences, Ulster University, Coleraine, Northern Ireland, UK
Patrik Rorsman: Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 7LE, UK; Institute of Neuroscience and Physiology, Department of Physiology, Metabolic Research Unit, Sahlgrenska Academy, University of Gothenburg, Box 430, S-405 30 Gothenburg, Sweden; Biomedical Sciences Research Institute, School of Biomedical Sciences, Ulster University, Coleraine, Northern Ireland, UK
Quan Zhang: Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 7LE, UK; CNC - Center for Neuroscience and Cell Biology, CIBB - Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal; Corresponding author

Journal volume & issue: Vol. 27, no. 5
p. 109665

Abstract

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Summary: 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.

Published in iScience

ISSN: 2589-0042 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Science
Website: http://www.cell.com/iscience/home

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