Cited by 136Pancreatic function and diabetesCellular transport and secretionNeuroscience and Neuropharmacology Research

Regulated Exocytosis of GABA-containing Synaptic-like Microvesicles in Pancreatic β-cells

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Braun, Matthias, Wendt, Anna, Birnir, Bryndis, Broman, Jonas, Eliasson, Lena, Galvanovskis, Juris, Gromada, Jesper, Mulder, Hindrik +1 more·2004·The Journal of General Physiology

Abstract

We have explored whether γ-aminobutyric acid (GABA) is released by regulated exocytosis of GABA-containing synaptic-like microvesicles (SLMVs) in insulin-releasing rat pancreatic β-cells. To this end, β-cells were engineered to express GABAA-receptor Cl−-channels at high density using adenoviral infection. Electron microscopy indicated that the average diameter of the SLMVs is 90 nm, that every β-cell contains ∼3,500 such vesicles, and that insulin-containing large dense core vesicles exclude GABA. Quantal release of GABA, seen as rapidly activating and deactivating Cl−-currents, was observed during membrane depolarizations from −70 mV to voltages beyond −40 mV or when Ca2+ was dialysed into the cell interior. Depolarization-evoked GABA release was suppressed when Ca2+ entry was inhibited using Cd2+. Analysis of the kinetics of GABA release revealed that GABA-containing vesicles can be divided into a readily releasable pool and a reserve pool. Simultaneous measurements of GABA release and cell capacitance indicated that exocytosis of SLMVs contributes ∼1% of the capacitance signal. Mathematical analysis of the release events suggests that every SLMV contains 0.36 amol of GABA. We conclude that there are two parallel pathways of exocytosis in pancreatic β-cells and that release of GABA may accordingly be temporally and spatially separated from insulin secretion. This provides a basis for paracrine GABAergic signaling within the islet.

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Crossref · 10.1085/jgp.200308966

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  • β-cells have been genetically engineered for detection of ATP, GABA or glycine release by adenoviral infection with ATP-activated P2X2 receptors, GABAA receptors or glycine receptors.

    “For example, β-cells have been genetically engineered for detection of ATP, GABA or glycine release by adenoviral infection with ATP-activated P2X2 receptors (P2X2R) (484), GABAA receptors (GABAAR) (93) or glycine receptors (GlyR) (744).”
  • Pancreatic β-cells have an intracellular chloride concentration as high as 35 mM, predicting a Cl- reversal potential of -35 mV, so opening of Cl- channels at more negative potentials will result in Cl- influx and membrane depolarization.

    “Pancreatic β-cells have an intracellular chloride concentration ([Cl-]i) as high as 35 mM (93). This predicts a Cl- reversal potential (ECl) of -35 mV, and argues that at more negative potentials opening of Cl- channels will result in Cl- influx, and thus membrane depolarization.”

    From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [93]

    The citation is attached to the claim that pancreatic β-cells have an intracellular chloride concentration as high as 35 mM. Our copy does not report that concentration: the Discussion gives a chloride equilibrium potential of −43 mV, while the Results describe 23 mM intracellular chloride in an experimental solution. A search for 35 mM intracellular chloride found no supporting passage. (LLM, conf=0.76)

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  • It is unlikely that insulin or Zn2+ co-secreted from beta cell granules or GABA from beta cell microvesicles contribute to inhibition of glucagon secretion by up to 7 mmol/l glucose.

    “Consequently, it is unlikely that insulin or Zn 2+ co-secreted from the same beta cell granules or the similarly regulated release of GABA from beta cell microvesicles [36] contribute to inhibition of glucagon secretion by up to 7 mmol/l glucose.”

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Authors
Braun, M., Wendt, A., Birnir, B., Broman, J., Eliasson, L., Galvanovskis, J., Gromada, J., Mulder, H., & Rorsman, P.
Affiliations
  • Lund University (SE)
  • 3Lilly Research Laboratories, Lilly Forschung GmbH, D-22419 Hamburg, Germany
Corresponding author
Braun, Matthias
Venue
The Journal of General Physiology
Published
2004-02-09
Volume
123
Issue
3
Pages
191-204
ISSN
  • 0022-1295 (ISSN-L)
  • 1540-7748
OpenAlex
W2128115766
Cited by
130
References
58
Citations by year
2026: 2 · 2025: 4 · 2024: 5 · 2023: 2 · 2022: 4 · 2021: 3 · 2020: 4 · 2019: 6 · 2018: 3 · 2017: 3 · 2016: 3 · 2015: 6 · 2014: 9 · 2013: 12 · 2012: 5
FWCI
11.72
Type
journal article
Language
en
Open access
Locations
  • The Journal of General Physiology (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
  • PubMed Central (publishedVersion, cc-by-nc-sa)
  • PubMed (publishedVersion)
  • Lund University Publications (Lund University) (submittedVersion, other-oa)
Funders
Vetenskapsrådet
Topics
  • Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
GABA release, regulated exocytosis, synaptic-like microvesicles, pancreatic beta cells, quantal release, readily releasable pool, reserve pool, calcium-dependent exocytosis, islet, insulin secretion, large dense core vesicles
MeSH terms
Animals, Dose-Response Relationship, Drug, Exocytosis, gamma-Aminobutyric Acid, Humans, Islets of Langerhans, Receptors, GABA-A, Synaptic Vesicles, Rats, Sprague-Dawley, Rats, Wistar, Calcium Signaling, Rats, GABA-A Receptor Agonists

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