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

doi:10.1016/j.isci.2024.109665

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

Faculty Of Life & Health Sciences

Research output: Contribution to journal › Article › peer-review

3 Citations (Scopus)

51 Downloads (Pure)

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 language	English
Article number	109665
Pages (from-to)	1-19
Number of pages	19
Journal	iScience
Volume	27
Issue number	5
Early online date	5 Apr 2024
DOIs	https://doi.org/10.1016/j.isci.2024.109665
Publication status	Published (in print/issue) - 17 May 2024

Bibliographical note

Publisher Copyright:
© 2024 The Author(s)

Funding

We thank Dr M Chibalina (University of Oxford) for help with cloning of R-CEPIA1er construct. We also thank Dr M Brereton (University of Oxford) and Dr E Coutinho (University of Coimbra and Cat\u00F3lica Medical School) for discussions. This study was supported by a Diabetes UK RD Lawrence Fellowship (QZ, 14/0005128), an EFSD European Research Program on New Targets for Type 2 Diabetes supported by an educational research grant from MSD (Q.Z. 96406), a John Fell Fund project grant (Q.Z. 152/052), the RCUK Medical Research Council (PR, MR/VO11979/1), the Leona M. and Harry B. Helmsley Charitable Trust (PR, G-1912-03553& G-2305-06047), and a project grant from the National Natural Science Foundation of China (82200887) to R.G. J.M. is supported by a visiting fellowship from Chinese Scholarship Council (CSC; 202106240129). Q.Z. conceived the study. S.A. J.M. G.D. R.G. and Q.Z. conducted experiments and analyzed data. S.A. wrote the first draft of the manuscript. Q.Z. reviewed and edited the manuscript. All authors discussed the data and edited the manuscript. Q.Z. and P.R. secured funding. Q.Z. is the guarantor of this work and, as such, has full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. The authors declare no competing interests. We thank Dr M Chibalina (University of Oxford) for help with cloning of R-CEPIA1er construct. We also thank Dr M Brereton (University of Oxford) and Dr E Coutinho (University of Coimbra and Cat\u00F3lica Medical School) for discussions. This study was supported by a Diabetes UK RD Lawrence Fellowship (QZ, 14/0005128 ), an EFSD European Research Program on New Targets for Type 2 Diabetes supported by an educational research grant from MSD (Q.Z., 96406 ), a John Fell Fund project grant (Q.Z., 152/052 ), the RCUK Medical Research Council (PR, MR/VO11979/1 ), the Leona M. and Harry B. Helmsley Charitable Trust (PR, G-1912-03553 & G-2305-06047 ), and a project grant from the National Natural Science Foundation of China ( 82200887 ) to R.G.. J.M. is supported by a visiting fellowship from Chinese Scholarship Council (CSC; 202106240129 ).

Funders	Funder number
European Foundation for the Study of Diabetes
Medical Research Council	MR/VO11979/1
Medical Research Council
Diabetes UK	14/0005128
Diabetes UK
G-2305-06047
National Natural Science Foundation of China	82200887
National Natural Science Foundation of China
University of Oxford	Q.Z. 152/052, 152/052
University of Oxford
China Scholarship Council	202106240129
China Scholarship Council

Keywords

Cell biology
Cellular physiology
Physiology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.isci.2024.109665

PIIS2589004224008873Final published version, 2.28 MBLicence: CC BY

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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.",

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AU - Denwood, Geoffrey

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AU - Tarasov, Andrei

AU - Rorsman, Patrik

AU - Zhang, Quan

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N2 - 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.

AB - 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.

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KW - Cellular physiology

KW - Physiology

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

Abstract

Bibliographical note

Funding

Keywords

UN SDGs

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