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Role of cytosolic and endoplasmic reticulum Ca2+ in pancreatic beta-cells: pros and cons

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Pflügers Archiv - European Journal of Physiology Aims and scope Submit manuscript

Abstract

Pancreatic beta cells utilize Ca2+ to secrete insulin in response to glucose. The glucose-dependent increase in cytosolic Ca2+ concentration ([Ca2+]C) activates a series of insulin secretory machinery in pancreatic beta cells. Therefore, the amount of insulin secreted in response to glucose is determined in a [Ca2+]C-dependent manner, at least within a moderate range. However, the demand for insulin secretion may surpass the capability of beta cells. Abnormal elevation of [Ca2+]C levels beyond the beta-cell endurance capacity can damage them by inducing endoplasmic reticulum (ER) stress and cell death programs such as apoptosis. Therefore, while Ca2+ is essential for the insulin secretory functions of beta cells, it could affect their survival at pathologically higher levels. Because an increase in beta-cell [Ca2+]C is inevitable under certain hazardous conditions, understanding the regulatory mechanism for [Ca2+]C is important. Therefore, this review discusses beta-cell function, survival, ER stress, and apoptosis associated with intracellular and ER Ca2+ homeostasis.

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Abbreviations

ATP:

Adenosine triphosphate

AMP:

Adenosine monophosphate

BiPS:

Binding immunoglobulin protein

cAMP:

Cyclic AMP

CRE:

CAMP-response element

CREB:

CAMP-response element binding protein

CRAC:

Ca2+ release–activated Ca2+

EPAC:

Exchange protein directly activated by cAMP

eIF2α:

Eukaryotic initiation factor 2α

ER:

Endoplasmic reticulum

ERAD:

ER-associated protein degradation

GDP:

Guanosine diphosphate

GTP:

Guanosine triphosphate

GEF:

Guanine nucleotide exchange factor

GLUT:

Glucose transporters

GSIS:

Glucose-stimulated insulin secretion

GPCRs:

Guanine-nucleotide-binding regulatory protein (G protein)-coupled receptors

GLP:

Glucagon-like peptide

GIP:

Glucose-dependent insulinotropic polypeptide

GRP:

Glucose-regulated protein

HOMA:

Homeostasis model assessment

HSPA:

Heat shock 70 kDa protein

Kir:

Inwardly-rectifying potassium channels

IICR:

IP3-induced Ca2+ release

IRE1:

Inositol-requiring 1

JNK:

C-Jun N-terminal kinase

KATP :

ATP-sensitive K+

KV :

Voltage-dependent K+

MA:

Malate-aspartate

PERK:

Protein kinase RNA-like ER kinase

Pyk:

Protein tyrosine kinase

PHHI:

Persistent hyperinsulinemic hypoglycemia in infants

PKA:

Protein kinase A

ROS:

Reactive oxygen species

RyR:

Ryanodine receptors

RAP:

Ras-related protein

SUR:

Sulfonylurea receptors

SERCA:

Sarco/-endoplasmic reticulum Ca2+ ATPase

SOCE:

Store-operated calcium entry

Stim:

Stromal interaction molecule

SARAF:

SOCE-associated regulatory factor

TRP:

Transient receptor potential

UPR:

Unfolded protein response

VDCC:

Voltage-dependent Ca2+ channels

WFS:

Wolfram syndrome

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Funding

This study was supported by grants from the National Research Foundation of Korea (NRF) Grant funded by the Korean Government (MSIP) (Grant No. 2021R1A2C2004171, 2021R1C1C2011264, 2021R1A2C1011233) and the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI) funded by the Ministry of Health and Welfare, Republic of Korea (Grant No. HI14C1324).

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Authors and Affiliations

  1. Department of Physiology & Obesity-Mediated Disease Research Center, Keimyung University School of Medicine, 1095 Dalgubeol-Daeroro, Dalseo-Gu, Daegu, 42601, South Korea

    Seung-Eun Song, Hyeon Yeong Ju, Seung-Soon Im & Dae-Kyu Song

  2. Department of Food Science and Nutrition, Kyungpook National University, Daegu, South Korea

    Su-Kyung Shin

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  1. Seung-Eun Song
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  2. Su-Kyung Shin
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  3. Hyeon Yeong Ju
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  4. Seung-Soon Im
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  5. Dae-Kyu Song
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Contributions

S.S.E. and I.S.S. organized and reviewed the manuscript. S.S.K. and J.H.Y. drew the figures. S.D.K. organized and wrote the manuscript.

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Correspondence to Dae-Kyu Song.

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Song, SE., Shin, SK., Ju, H.Y. et al. Role of cytosolic and endoplasmic reticulum Ca2+ in pancreatic beta-cells: pros and cons. Pflugers Arch - Eur J Physiol 476, 151–161 (2024). https://doi.org/10.1007/s00424-023-02872-2

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