Suppression of Sulfonylurea- and Glucose-Induced Insulin Secretion In Vitro and In Vivo in Mice Lacking the Chloride Transport Protein ClC-3
Open accessAbstract
Priming of insulin secretory granules for release requires intragranular acidification and depends on vesicular Cl(-)-fluxes, but the identity of the chloride transporter/ion channel involved is unknown. We tested the hypothesis that the chloride transport protein ClC-3 fulfills these actions in pancreatic beta cells. In ClC-3(-/-) mice, insulin secretion evoked by membrane depolarization (high extracellular K(+), sulfonylureas), or glucose was >60% reduced compared to WT animals. This effect was mirrored by a approximately 80% reduction in depolarization-evoked beta cell exocytosis (monitored as increases in cell capacitance) in single ClC-3(-/-) beta cells, as well as a 44% reduction in proton transport across the granule membrane. ClC-3 expression in the insulin granule was demonstrated by immunoblotting, immunostaining, and negative immuno-EM in a high-purification fraction of large dense-core vesicles (LDCVs) obtained by phogrin-EGFP labeling. The data establish the importance of granular Cl(-) fluxes in granule priming and provide direct evidence for the involvement of ClC-3 in the process.
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β-cells from Clcn3 knockout mice show normal [Ca2+]i responses to glucose, suggesting that any ClC3 transporters that reach the plasma membrane do not provide the depolarizing inward current.
“However, the fact that β-cells from Clcn3 knockout mice show normal [Ca2+]i responses to glucose (389), suggests that any ClC3 transporters that reach the plasma membrane do not provide the depolarizing inward current.”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [389]
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- Authors
- Li, D.-Q., Jing, X., Salehi, A., Collins, S. C., Hoppa, M. B., Rosengren, A. H., Zhang, E., Lundquist, I., Olofsson, C. S., Mörgelin, M., Eliasson, L., Rorsman, P., & Renström, E.
- Affiliations
- Lund University (SE)
- University of Oxford (GB)
- University of Gothenburg (SE)
- Corresponding author
- Renström, Erik
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2009-10
- Volume
- 10
- Issue
- 4
- Pages
- 309-315
- ISSN
- 1550-4131 (ISSN-L)
- OpenAlex
- W1986559207
- Cited by
- 50
- References
- 0
- Citations by year
- 2025: 2 · 2024: 2 · 2023: 2 · 2022: 3 · 2021: 3 · 2019: 5 · 2018: 2 · 2017: 4 · 2016: 1 · 2014: 8 · 2013: 2 · 2012: 8
- FWCI
- 5.38
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Lund University Publications (Lund University) (submittedVersion, other-oa)
- Funders
- Knut och Alice Wallenbergs Stiftelse
- Vetenskapsrådet
- Wellcome Trust
- European Foundation for the Study of Diabetes
- Novo Nordisk Fonden
- Topics
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion Transport and Channel Regulation
- Keywords
- ClC-3, chloride transport, insulin secretion, pancreatic beta cells, insulin secretory granules, proton transport, sulfonylureas, glucose-stimulated insulin secretion, membrane depolarization, large dense core vesicles
- MeSH terms
- Insulin Secretion, Animals, Calcium, Chlorides, Cytoplasmic Granules, Glucose, Insulin, Sulfonylurea Compounds, Chloride Channels, Mice, Knockout, RNA Interference, Insulin-Secreting Cells, Mice, Glucagon-Like Peptide 1
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