K+ channel and alpha 2-adrenergic effects on glucose-induced Ca2+i surges: aberrant behavior in ob/ob mice.
Glucose-induced shifts in intracellular free Ca2+ concentration ([Ca2+]i) were quantitatively and temporally the same in ob/ob and +/+ beta-cells. In both, epinephrine promptly and protractedly inhibited the glucose-induced [Ca2+]i surge via a pertussis toxin-sensitive alpha 2-adrenergic mechanism that was reversible by potassium depolarization. When added before glucose, epinephrine blocked completely in the ob/ob beta-cells, but in the +/+ beta-cells it produced a delayed, reduced, and transient intracellular Ca2+ (Ca2+i) surge. Neither the ATP-sensitive K+ channel blocker tolbutamide nor the large-conductance Ca(2+)-activated K+ channel (Kmaxi) blocker charybdotoxin reversed the effect of epinephrine. Tetraethylammonium (TEA), a blocker of both the Kmaxi and the delayed-rectifier K+ channel, and forskolin attenuated the effect of epinephrine in +/+ but not in the ob/ob beta-cells. The data show that 1) alpha 2-adrenoreceptor activation decreases the glucose-stimulated Ca2+i surge in +/+ beta-cells primarily by activating a tolbutamide- and charybdotoxin-insensitive, TEA- and forskolin-sensitive K+ channel; 2) the hypersecretion of insulin in ob/ob beta-cells is not due to enhanced glucose-induced Ca2+ influx; and 3) the ob/ob beta-cells are aberrant with regard to alpha 2-adrenergic modulation.
Department of Biochemistry, University of Ottawa, Ontario, Canada.
L
L
Fournier
J F
JF
Whitfield
H
H
Xiang
J L
JL
Schwartz
N
N
Bégin-Heick
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D000242:Cyclic AMP / Q000502:physiology; D004837:Epinephrine / Q000494:pharmacology; D005947:Glucose / Q000494:pharmacology*; D007515:Islets of Langerhans / Q000378:metabolism; D008297:Male; D008564:Membrane Potentials; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009154:Mutation; D009765:Obesity / Q000235:genetics / Q000378:metabolism*; D037342:Pertussis Toxin; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism*; D013566:Sympathomimetics / Q000494:pharmacology*; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D002121:Calcium Channel Blockers; D015221:Potassium Channels; D013566:Sympathomimetics; D010566:Virulence Factors, Bordetella; D000242:Cyclic AMP; D037342:Pertussis Toxin; D005947:Glucose; D002118:Calcium; D004837:Epinephrine