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Cited by 118Pancreatic function and diabetesIon channel regulation and functionIon Channels and Receptors

A store-operated mechanism determines the activity of the electrically excitable glucagon-secreting pancreatic α-cell

Liu, Yi-Jia, Vieira, Elaine, Gylfe, Erik·2004·Cell Calcium
DOI 10.1016/j.ceca.2003.10.002
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Abstract

The glucagon-releasing pancreatic alpha-cells are electrically excitable cells but the signal transduction leading to depolarization and secretion is not well understood. To clarify the mechanisms we studied [Ca(2+)](i) and membrane potential in individual mouse pancreatic alpha-cells using fluorescent indicators. The physiological secretagogue l-adrenaline increased [Ca(2+)](i) causing a peak, which was often followed by maintained oscillations or sustained elevation. The early effect was due to mobilization of Ca(2+) from the endoplasmic reticulum (ER) and the late one to activation of store-operated influx of the ion resulting in depolarization and Ca(2+) influx through voltage-dependent L-type channels. Consistent with such mechanisms, the effects of adrenaline on [Ca(2+)](i) and membrane potential were mimicked by inhibitors of the sarco(endo)plasmic reticulum Ca(2+) ATPase. The alpha-cells express ATP-regulated K(+) (K(ATP)) channels, whose activation by diazoxide leads to hyperpolarization. The resulting inhibition of the voltage-dependent [Ca(2+)](i) response to adrenaline was reversed when the K(ATP) channels were inhibited by tolbutamide. However, tolbutamide alone rarely affected [Ca(2+)](i), indicating that the K(ATP) channels are normally closed in mouse alpha-cells. Glucose, which is the major physiological inhibitor of glucagon secretion, hyperpolarized the alpha-cells and inhibited the late [Ca(2+)](i) response to adrenaline. At concentrations as low as 3mM, glucose had a pronounced stimulatory effect on Ca(2+) sequestration in the ER amplifying the early [Ca(2+)](i) response to adrenaline. We propose that adrenaline stimulation and glucose inhibition of the alpha-cell involve modulation of a store-operated current, which controls a depolarizing cascade leading to opening of L-type Ca(2+) channels. Such a control mechanism may be unique among excitable cells.

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  • Exposure to SERCA inhibitors CPA and thapsigargin activates a store-operated cation influx resulting in alpha cell depolarisation and voltage-dependent [Ca2+]i signalling.

    “We recently demonstrated that exposure to the sarco(endo)plasmic reticulum Ca 2+ ATPase (SERCA) inhibitors CPA and thapsigargin activates a store-operated cation influx resulting in alpha cell depolarisation and voltage-dependent [Ca 2+ ] i signalling [15].”

    From Glucose inhibits glucagon secretion by a direct effect on mouse pancreatic alpha cells (2007) · cites this paper as [15]

  • Glucose regulates glucagon secretion by a Ca2+ store-operated mechanism.

    “We recently proposed that glucose regulates glucagon secretion by a Ca 2+ store-operated mechanism [15].”

    From Glucose inhibits glucagon secretion by a direct effect on mouse pancreatic alpha cells (2007) · cites this paper as [15]

  • In the absence of voltage-dependent Ca2+ entry, activation of the store-operated pathway results in a modest rise of [Ca2+]i in alpha cells.

    “In the absence of voltage-dependent Ca 2+ entry, activation of the store-operated pathway results in a modest rise of [Ca 2+ ] i in alpha cells [15].”

    From Glucose inhibits glucagon secretion by a direct effect on mouse pancreatic alpha cells (2007) · cites this paper as [15]

  • These data are consistent with stimulated sequestration and outward transport of Ca2+ being saturated at lower glucose concentrations in alpha-cells than in beta-cells.

    “These data are consistent with stimulated sequestration and outward transport of Ca 2ϩ (14,20,21) being saturated at lower glucose concentrations in ␣-cells (14) than in ␤-cells (21).”

    From Paradoxical Stimulation of Glucagon Secretion by High Glucose Concentrations (2006) · cites this paper as [14]

  • Only alpha-cells confirmed by immunostaining were included in the analyses.

    “Only ␣-cells confirmed by immunostaining were included in the analyses (14).”

    From Paradoxical Stimulation of Glucagon Secretion by High Glucose Concentrations (2006) · cites this paper as [14]

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Authors
Liu, Y.-J., Vieira, E., & Gylfe, E.
Affiliations
Uppsala University (SE)
Corresponding author
Gylfe, Erik
ORCID
Venue
Cell Calcium
Publisher
Elsevier BV
Published
2004-04
Volume
35
Issue
4
Pages
357-365
ISSN
0143-4160 (ISSN-L)
DOI
10.1016/j.ceca.2003.10.002
OpenAlex
W2064908943
Cited by
118
References
49
Citations by year
2026: 3 · 2025: 3 · 2024: 1 · 2023: 6 · 2022: 3 · 2021: 8 · 2020: 6 · 2019: 6 · 2018: 4 · 2017: 2 · 2016: 8 · 2015: 3 · 2014: 10 · 2013: 8 · 2012: 3
FWCI
5.75
Type
journal article
Language
en
Open access
closed
Licence
Locations
  • Cell Calcium (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
  • Life Sciences › Neuroscience › Sensory Systems › Ion Channels and Receptors
Keywords
alpha cells, glucagon secretion, store-operated calcium entry, epinephrine, glucose, endoplasmic reticulum calcium, L-type calcium channels, ATP-sensitive potassium channels, tolbutamide, diazoxide, sarco/endoplasmic reticulum Ca2+-ATPase, membrane potential, calcium oscillations, excitable cells
MeSH terms
Animals, Calcium, Endoplasmic Reticulum, Epinephrine, Glucagon, Glucose, Islets of Langerhans, Membrane Potentials, Vasoconstrictor Agents, Calcium Channels, Potassium Channels, Calcium Signaling, Mice

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