Resveratrol inhibits electrical activity and insulin release from insulinoma cells by block of voltage-gated Ca+ channels and swelling-dependent Cl- currents.
The phytostilbene resveratrol (RV) improves the metabolic state in animal models by increasing the insulin responsiveness of tissues and there is evidence that RV affects insulin secretion from native beta-cells and insulinoma cells. In whole cell patch clamp experiments on clonal rat INS-1E cells we used high extracellular glucose (20 mM), extracellular hypotonicity (30%) or tolbutamide (100 microM) to elicit membrane depolarizations and electrical activity. Application of RV (50 microM) repolarized the cells, terminated electrical activity and prevented the hypotonicity-induced depolarization. These effects were fully reversible and intermittent application of RV restored tolbutamide-induced electrical activity after desensitization. Glucose-induced depolarization was counteracted by RV in presence of iberiotoxin (50 nM), showing that the RV effect does not depend on BK(Ca) channel activation. RV dose-dependently inhibited K(ATP) currents, L- and T-type Ca(2+) currents and swelling-dependent Cl(-) currents evoked by either hypotonicity or high extracellular glucose--ion conductances crucially involved in regulating the electrical activity of insulin secreting cells. We further show that RV blunts glucose-induced, but not basal insulin release. Our results indicate that RV counteracts/prevents stimulus-induced cell membrane depolarization and electrical activity by blocking voltage-gated Ca(2+)- and swelling-dependent Cl(-) currents despite the inhibition of K(ATP) currents.
Jakab
Martin
M
Institute of Physiology and Pathophysiology, Paracelsus Medical University, Salzburg, Austria.
Lach
Sibylle
S
Bacová
Zuzana
Z
Langelüddecke
Christian
C
Strbák
Vladimir
V
Schmidt
Sabine
S
Iglseder
Eva
E
Paulmichl
Markus
M
Geibel
John
J
Ritter
Markus
M
D000818:Animals; D015220:Calcium Channels / Q000378:metabolism*; D018118:Chloride Channels / Q000378:metabolism*; D005947:Glucose / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007340:Insulinoma / Q000378:metabolism*; D015640:Ion Channel Gating / Q000187:drug effects*; D009543:Nifedipine / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D010455:Peptides / Q000494:pharmacology; D051381:Rats; D000077185:Resveratrol; D012996:Solutions; D013267:Stilbenes / Q000494:pharmacology*; D014044:Tolbutamide / Q000494:pharmacology
D015220:Calcium Channels; D018118:Chloride Channels; D007328:Insulin; D010455:Peptides; D012996:Solutions; D013267:Stilbenes; C064719:iberiotoxin; D014044:Tolbutamide; D009543:Nifedipine; D005947:Glucose; D000077185:Resveratrol