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Cited by 67Pancreatic function and diabetesIon channel regulation and functionCardiac electrophysiology and arrhythmias

Pharmacological Properties and Functional Role of Kslow Current in Mouse Pancreatic β-Cells

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Min Zhang, Khaled M. Houamed, Sabina Kupershmidt, Dan M. Roden, Leslie S. Satin·2005·The Journal of General Physiology
DOI 10.1085/jgp.200509312PMC PMC2266621
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Abstract

The pharmacological properties of slow Ca2+-activated K+ current (Kslow) were investigated in mouse pancreatic β-cells and islets to understand how Kslow contributes to the control of islet bursting, [Ca2+]i oscillations, and insulin secretion. Kslow was insensitive to apamin or the KATP channel inhibitor tolbutamide, but UCL 1684, a potent and selective nonpeptide SK channel blocker reduced the amplitude of Kslow tail current in voltage-clamped mouse β-cells. Kslow was also selectively and reversibly inhibited by the class III antiarrythmic agent azimilide (AZ). In isolated β-cells or islets, pharmacologic inhibition of Kslow by UCL 1684 or AZ depolarized β-cell silent phase potential, increased action potential firing, raised [Ca2+]i, and enhanced glucose-dependent insulin secretion. AZ inhibition of Kslow also supported mediation by SK, rather than cardiac-like slow delayed rectifier channels since bath application of AZ to HEK 293 cells expressing SK3 cDNA reduced SK current. Further, AZ-sensitive Kslow current was extant in β-cells from KCNQ1 or KCNE1 null mice lacking cardiac slow delayed rectifier currents. These results strongly support a functional role for SK channel-mediated Kslow current in β-cells, and suggest that drugs that target SK channels may represent a new approach for increasing glucose-dependent insulin secretion. The apamin insensitivity of β-cell SK current suggests that β-cells express a unique SK splice variant or a novel heteromultimer consisting of different SK subunits.

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  • Azimilide appears to be a specific blocker of the SK3 channel in mouse β-cells, and increases the duration of the slow waves and potentiates GIIS.

    “Azimilide appears to be a specific blocker of the SK3 channel in mouse β-cells (759), and increases the duration of the slow waves and potentiates GIIS (759).”

    From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [759]

    The Results report that azimilide blocks β-cell Kslow current, increases islet bursting, and inhibits SK3 channels expressed in HEK cells; the Introduction reports enhanced glucose-dependent insulin secretion. But the Discussion says SK3 is unlikely to be the isoform mediating Kslow in β-cells, so the paper does not establish azimilide as a specific SK3 blocker there. The Results describe shorter repolarizing events, not an increase in slow-wave duration. Page numbers are unavailable in our copy. (LLM, conf=0.87)

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Authors
Zhang, M., Houamed, K. M., Kupershmidt, S., Roden, D. M., & Satin, L. S.
Affiliations
  • Virginia Commonwealth University (US)
  • University of Chicago (US)
  • Vanderbilt University Medical Center (US)
ORCID
Venue
The Journal of General Physiology
Publisher
Rockefeller University Press
Published
2005-09-26
Volume
126
Issue
4
Pages
353-363
ISSN
  • 0022-1295 (ISSN-L)
  • 1540-7748
DOI
10.1085/jgp.200509312
PMC
PMC2266621
OpenAlex
W2154712565
Cited by
67
References
2
Citations by year
2024: 2 · 2023: 1 · 2022: 1 · 2021: 2 · 2019: 1 · 2018: 3 · 2017: 4 · 2016: 2 · 2015: 1 · 2014: 8 · 2013: 4 · 2012: 6
FWCI
3.93
Type
journal article
Language
en
Open access
Licence
cc-by-nc-sa
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)
Funders
National Institute of Diabetes and Digestive and Kidney Diseases (R01DK046409)
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
small conductance calcium-activated potassium channels, pancreatic beta cells, azimilide, calcium oscillations, glucose-dependent insulin secretion, KCNQ1, KCNE1
MeSH terms
Alkanes, Animals, Calcium, Calcium Channel Blockers, Cell Line, Dose-Response Relationship, Drug, Glucose, Humans, Hydantoins, Insulin, Membrane Potentials, Piperazines, Potassium, Quinolinium Compounds, Time Factors, Transfection, Mice, Knockout, Potassium Channels, Voltage-Gated, Imidazolidines, Insulin-Secreting Cells, Mice, Small-Conductance Calcium-Activated Potassium Channels, KCNQ1 Potassium Channel

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