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Metabolic Stress Shifts the Function of KCa3.1 Channels in Pancreatic Beta Cells From a Regulator of Membrane Potential to a Proapoptotic Factor.

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Τίτλος: Metabolic Stress Shifts the Function of KCa3.1 Channels in Pancreatic Beta Cells From a Regulator of Membrane Potential to a Proapoptotic Factor.
Συγγραφείς: Hense J; Institute of Pharmaceutical and Medicinal Chemistry, Department of Pharmacology, University of Münster, Münster, Germany., Beuke L; Institute of Pharmaceutical and Medicinal Chemistry, Department of Pharmacology, University of Münster, Münster, Germany., Kick C; Institute of Pharmaceutical and Medicinal Chemistry, University of Münster, Münster, Germany., Wünsch B; Institute of Pharmaceutical and Medicinal Chemistry, University of Münster, Münster, Germany., Düfer M; Institute of Pharmaceutical and Medicinal Chemistry, Department of Pharmacology, University of Münster, Münster, Germany.
Πηγή: Archiv der Pharmazie [Arch Pharm (Weinheim)] 2026 Oct; Vol. 359 (10), pp. e70344.
Τύπος έκδοσης: Journal Article
Γλώσσα: English
Στοιχεία περιοδικού: Publisher: Wiley-VCH Verlag GmbH & Co. KGaA Country of Publication: Germany NLM ID: 0330167 Publication Model: Print Cited Medium: Internet ISSN: 1521-4184 (Electronic) Linking ISSN: 03656233 NLM ISO Abbreviation: Arch Pharm (Weinheim) Subsets: MEDLINE
Imprint Name(s): Publication: <2005->: Weinheim Germany : Wiley-VCH Verlag GmbH & Co. KGaA
Original Publication: Weinheim, Verlag Chemie GmbH.
Ιατρικοί όροι (MeSH): Intermediate-Conductance Calcium-Activated Potassium Channels*/metabolism , Intermediate-Conductance Calcium-Activated Potassium Channels*/antagonists & inhibitors , Insulin-Secreting Cells*/metabolism , Insulin-Secreting Cells*/drug effects , Apoptosis*/drug effects , Stress, Physiological*, Membrane Potentials/drug effects ; Glucose/pharmacology ; Glucose/metabolism ; Membrane Potential, Mitochondrial/drug effects ; Triphenylmethyl Compounds/pharmacology ; Calcium Channels, L-Type/metabolism ; Animals ; Mice ; Cells, Cultured ; Acetamides
Περίληψη: Metabolic stress increases the whole-cell current through KCa3.1 channels in mouse pancreatic islet cells. The study aimed to analyze the network between ion channels mediating Ca2+ influx for KCa3.1 channel activation and stress-related changes. The physiologically important Kslow current of beta cells was not altered in total but the contribution of KCa3.1 current was reduced after culture in the presence of high glucose and palmitate concentrations. Electrical activity was increased by blocking KCa3.1 channels with senicapoc in islets cultured under standard conditions but not after metabolic stress. Of note, the functional coupling of KCa3.1 to l-type Ca2+ channels was severely reduced by metabolic stress, whereas the coupling to Ca2+-influx via NMDA receptors increased. Mitochondrial membrane potential of beta cells was not affected by senicapoc but by a mitochondria-targeted derivative. Inhibition of KCa3.1 channels by senicapoc or maurotoxin partly protected from apoptosis. In conclusion, the data indicate a shift in the interplay of Ca2+-conducting ion channels and the plasma membrane-localized KCa3.1 channel. KCa3.1 channels changed from an important regulator of membrane potential oscillations to a dysfunctional and proapoptotic factor. This switch might be involved in the decline of islet cell mass and function during progression of type 2 diabetes mellitus.
(© 2026 The Author(s). Archiv der Pharmazie published by Wiley‐VCH GmbH on behalf of Deutsche Pharmazeutische Gesellschaft.)
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Contributed Indexing: Keywords: KCa3.1 channel; NMDA receptor; electrophysiology; glucolipotoxicity; pancreatic islet
Substance Nomenclature: 0 (Intermediate-Conductance Calcium-Activated Potassium Channels)
IY9XDZ35W2 (Glucose)
0 (Kcnn4 protein, mouse)
TS6G201A6Q (senicapoc)
0 (Triphenylmethyl Compounds)
0 (Calcium Channels, L-Type)
0 (Acetamides)
Entry Date(s): Date Created: 20261009 Date Completed: 20261009 Latest Revision: 20261011
Update Code: 20261011
PubMed Central ID: PMC13651915
DOI: 10.1002/ardp.70344
PMID: 42853522
Βάση Δεδομένων: MEDLINE
Περιγραφή
ISSN:1521-4184
DOI:10.1002/ardp.70344