The diabetogenic agent alloxan increases K+ permeability by a mechanism involving activation of ATP-sensitive K(+)-channels in mouse pancreatic beta-cells.
The effects of the diabetogenic agent, alloxan, on membrane potential, input resistance and electrical activity of normal mouse pancreatic beta-cells were studied. Tetraethylammonium (TEA), quinine and Glyburide were used to block K(+)-channels and to elucidate the mechanisms underlying alloxan's effects on beta-cell membrane potential. Exposure of the islet to alloxan (75-100 microM) in the presence of glucose (11 mM), produced a rapid (15 sec), transient inhibition of electrical activity, often accompanied by hyperpolarization of the membrane, and this was followed by recovery of the burst pattern. This early effect of alloxan was followed after approximately 15 min by a complete inhibition of electrical activity and hyperpolarization. The inhibition accompanied by hyperpolarization was associated with a decrease in input resistance, indicating increased K(+)-conductance. Both the transient and delayed effects of alloxan were blocked by glucose (33 mM), quinine and glyburide but not by other conditions which induce continuous electrical activity such as elevated external [K+] (10 mM), ouabain, K+ removal, or TEA (20 mM). The transient inhibition induced by alloxan may be due to a direct competition with glucose transport/metabolism since it did not occur when alpha-keto isocaproic acid (KIC) was used to induce electrical activity. The delayed inhibition may reflect indirect effects of accumulation of this agent or its metabolites within the cell. Since both effects of alloxan are blocked by glyburide they appear to involve activation of the ATP-sensitive K(+)-channel (K-ATP).
Carroll
P B
PB
Laboratory of Cell Biology and Genetics, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892.
Moura
A S
AS
Rojas
E
E
Atwater
I
I
D000496:Alloxan / Q000494:pharmacology*; D000818:Animals; D004553:Electric Conductivity; D004594:Electrophysiology; D005071:Evoked Potentials / Q000187:drug effects; D005260:Female; D005947:Glucose / Q000494:pharmacology; D005905:Glyburide / Q000494:pharmacology; D066298:In Vitro Techniques; D007515:Islets of Langerhans / Q000187:drug effects / Q000502:physiology*; D007700:Kinetics; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology*; D011803:Quinine / Q000494:pharmacology; D019789:Tetraethylammonium; D013757:Tetraethylammonium Compounds / Q000494:pharmacology; D013997:Time Factors
D026902:Potassium Channel Blockers; D015221:Potassium Channels; D013757:Tetraethylammonium Compounds; D019789:Tetraethylammonium; D000496:Alloxan; D011803:Quinine; D005947:Glucose; D005905:Glyburide