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Cited by 56Pancreatic function and diabetesIon channel regulation and functionCardiac electrophysiology and arrhythmias

Enhanced Glucose Tolerance by SK4 Channel Inhibition in Pancreatic β-Cells

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Düfer, Martina, Gier, Belinda, Wolpers, Daniela, Krippeit-Drews, Peter, Ruth, Peter, Drews, Gisela·2009·Diabetes
DOI 10.2337/db08-1324PMC PMC2712794
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Abstract

OBJECTIVE: Ca2+-regulated K+ channels are involved in numerous Ca2+-dependent signaling pathways. In this study, we investigated whether the Ca2+-activated K+ channel of intermediate conductance SK4 (KCa3.1, IK1) plays a physiological role in pancreatic β-cell function. RESEARCH DESIGN AND METHODS: Glucose tolerance and insulin sensitivity were determined in wild-type (WT) or SK4 knockout (SK4-KO) mice. Electrophysiological experiments were performed with the patch-clamp technique. The cytosolic Ca2+ concentration ([Ca2+]c) was determined by fura-2 fluorescence. Insulin release was assessed by radioimmunoassay, and SK4 protein was detected by Western blot analysis. RESULTS: SK4-KO mice showed improved glucose tolerance, whereas insulin sensitivity was not altered. The animals were not hypoglycemic. Isolated SK4-KO β-cells stimulated with 15 mmol/l glucose had an increased Ca2+ action potential frequency, and single-action potentials were broadened. These alterations were coupled to increased [Ca2+]c. In addition, glucose responsiveness of membrane potential, [Ca2+]c, and insulin secretion were shifted to lower glucose concentrations. SK4 protein was expressed in WT islets. An increase in K+ currents and concomitant membrane hyperpolarization could be evoked in WT β-cells by the SK4 channel opener DCEBIO (100 μmol/l). Accordingly, the SK4 channel blocker TRAM-34 (1 μmol/l) partly inhibited KCa currents and induced electrical activity at a threshold glucose concentration. In stimulated WT β-cells, TRAM-34 further increased [Ca2+]c and broadened action potentials similar to those seen in SK4-KO β-cells. SK4 channels were found to substantially contribute to Kslow (slowly activating K+ current). CONCLUSIONS: SK4 channels are involved in β-cell stimulus-secretion coupling. Deficiency of SK4 current induces elevated β-cell responsiveness and coincides with improved glucose tolerance in vivo. Therefore, pharmacologic modulation of these channels might provide an interesting approach for the development of novel insulinotropic drugs.

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  • β-cells from Kcnn4-deficient mice exhibit increased excitability, enhanced GIIS and improved glucose tolerance in vivo.

    “Although SK4 channels (Kcnn4) are expressed at low levels (only 5% of Kccn3), β-cells from Kcnn4-deficient mice exhibit increased excitability, enhanced GIIS and improved glucose tolerance in vivo (156).”

    From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [156]

  • The single-channel conductance of Kslow recorded with symmetrical 130 mM K+ solutions is 39 pS.

    “The single-channel conductance recorded with symmetrical 130 mM K+ solutions is 39 pS (156).”

    From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [156]

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Authors
Düfer, M., Gier, B., Wolpers, D., Krippeit-Drews, P., Ruth, P., & Drews, G.
Affiliations
  • University of Tübingen (DE)
  • From the Institute of Pharmacy, the Department of Pharmacology, University of Tübingen, Tübingen, Germany.
Corresponding author
Drews, Gisela
ORCID
Venue
Diabetes
Publisher
American Diabetes Association
Published
2009-04-28
Volume
58
Issue
8
Pages
1835-1843
ISSN
  • 0012-1797 (ISSN-L)
  • 1939-327X
DOI
10.2337/db08-1324
PMC
PMC2712794
OpenAlex
W2116424238
Cited by
56
References
4
Citations by year
2026: 1 · 2025: 2 · 2023: 1 · 2022: 2 · 2021: 6 · 2020: 2 · 2019: 3 · 2018: 4 · 2017: 5 · 2015: 6 · 2014: 6 · 2012: 6
FWCI
6.08
Type
journal article
Language
en
Open access
Licence
Locations
  • Diabetes (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Funders
Deutsche Forschungsgemeinschaft
Topics
  • Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
Keywords
KCa3.1, intermediate-conductance calcium-activated potassium channel, pancreatic beta cells, glucose tolerance, insulin secretion, stimulus-secretion coupling, intracellular calcium, membrane potential, TRAM-34, insulin sensitivity
MeSH terms
Animals, Blood Glucose, Crosses, Genetic, Female, Glucose Tolerance Test, Male, Mice, Inbred C57BL, Mice, Inbred Strains, Mice, Knockout, Insulin-Secreting Cells, Mice, Intermediate-Conductance Calcium-Activated Potassium Channels

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