NDLI: Direct effects of tolbutamide on mitochondrial function, intracellular Ca2+ and exocytosis in pancreatic β-cells

Content Provider	Springer Nature Link
Author	Smith, Paul A. Proks, Peter Moorhouse, Andrew
Copyright Year	1999
Abstract	Using the whole-cell voltage-clamp method to measure ATP-sensitive K+(KATP) currents, changes in cell capacitance to measure secretion and microfluorimetry to monitor intracellular Ca2+ and mitochondrial function, we have investigated the direct effect of sulphonylureas on exocytosis in pancreatic β-cells. Tolbutamide (100 µM) and 100 nM 4-β-12-phorbolmyristate-13-acetate (PMA), which activates the protein kinase C (PKC) isoforms found in β-cells, potentiated exocytosis in a non-additive manner. These effects were blocked by down-regulation of PKC. Our data support the idea that tolbutamide can potentiate secretion from β-cells via a PKC-dependent pathway. Because PKC and sulphonylureas can modulate the activity of KATP channels, we explored whether the above effects are caused by inhibition of this channel. PMA increased whole-cell KATP currents but did not affect their sensitivity to tolbutamide. Down-regulation of PKC affected neither the magnitude nor the tolbutamide sensitivity of the KATP current. Both tolbutamide and the mitochondrial uncoupler FCCP (1 µM) mobilized intracellular Ca2+ and prolonged Ca2+ transients elicited by cholinergic mobilization of intracellular Ca2+ stores. Tolbutamide (0.1–0.5 mM), like FCCP, depolarized the mitochondrial membrane potential and activated KATP currents. We suggest that sulphonylureas can directly potentiate exocytosis by impairing mitochondrial function and Ca2+ handling, which ultimately leads to activation of Ca2+-dependent enzymes such as PKC.
Starting Page	577
Ending Page	588
Page Count	12
File Format	PDF
ISSN	00316768
Journal	Pflügers Archiv
Volume Number	437
Issue Number	4
e-ISSN	14322013
Language	English
Publisher	Springer-Verlag
Publisher Date	1999-02-23
Publisher Place	Berlin, Heidelberg
Access Restriction	One Nation One Subscription (ONOS)
Content Type	Text
Resource Type	Article
Subject	Physiology Physiology (medical) Clinical Biochemistry

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